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Role of protein phosphatase 2A in kidney disease (Review)

  • Authors:
    • Lishi Shao
    • Yiqun Ma
    • Qixiang Fang
    • Ziye Huang
    • Shanshan Wan
    • Jiaping Wang
    • Li Yang
  • View Affiliations

  • Published online on: August 31, 2021
  • Article Number: 1236
  • Copyright: © Shao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Kidney disease affects millions of people worldwide and is a financial burden on the healthcare system. Protein phosphatase 2A (PP2A), which is involved in renal development and the function of ion‑transport proteins, aquaporin‑2 and podocytes, is likely to serve an important role in renal processes. PP2A is associated with the pathogenesis of a variety of different kidney diseases including podocyte injury, inflammation, tumors and chronic kidney disease. The current review aimed to discuss the structure and function of PP2A subunits in the context of kidney diseases. How dysregulation of PP2A in the kidneys causes podocyte death and the inactivation of PP2A in renal carcinoma tissues is discussed. Inhibition of PP2A activity prevents epithelial‑mesenchymal transition and attenuates renal fibrosis, creating a favorable inflammatory microenvironment and promoting the initiation and progression of tumor pathogenesis. The current review also indicates that PP2A serves an important role in protection against renal inflammation. Understanding the detailed mechanisms of PP2A provides information that can be utilized in the design and application of novel therapeutics for the treatment and prevention of renal diseases.

1. Introduction

Kidney disease, which is one of the fastest-growing causes of mortality worldwide, includes acute and chronic types that damage the structure and function of renal tissue (1). Acute kidney injury (AKI) and chronic kidney disease (CKD) are associated with increased risk of adverse cardiovascular events, as well as increased morbidity and mortality (2,3). These conditions can eventually develop into end-stage renal disease (ESRD) that requires dialysis or kidney replacement (4). The global economic cost of kidney disease is vast. In 2007, the United States Medicare expenditures on CKD exceeded $60,000,000 USD, accounting for 27% of the total Medicare budget (5), while expenditures on AKI exceed $10,000,000 USD per year (6). Therefore, elucidating the pathophysiological mechanisms of kidney disease will lead to the development of promising therapeutics for multiple renal diseases, which is essential to public health.

Reversible phosphorylation and dephosphorylation of proteins serve important roles in regulating protein activities and constitute the central mechanism of signal transduction (7). Protein phosphatase 2A (PP2A) enzymes are the main members of the serine/threonine (Ser/Thr) phosphatase family and are involved in the majority of total cellular-phosphatase activities (7). PP2A, which participates in a number of key pathways during all stages of the cell cycle, has been extensively studied in relation to tumor suppression (8). A growing body of literature suggests that PP2A is crucial in a number of aspects of renal-disease pathogenesis including AKI (9), CKD (10), aging (11) and tumorigenic processes (12). In the current review, the unique structure and function of PP2A is described and its interactions with associated signaling pathways in kidney disease are discussed. Therapeutic targeting of PP2A has demonstrated promise in enhancing the efficacy of treatments for patients with kidney disease.

2. Function of protein phosphatase in the kidneys

Protein phosphorylation and dephosphorylation are components of a vital mechanism used in the modulation of key cellular processes associated with cell proliferation, differentiation, migration and other biological behaviors involved in signaling regulation (13,14). Phosphatases are divided into four large families: i) Protein serine/threonine phosphatases [including the protein phosphatases (PPPs) and metal-dependent protein phosphatases], (2) protein tyrosine phosphatases (2), dual-specificity phosphatases (DUSP) and histidine phosphatases (3,4). As the largest of the Ser/Thr family, PPP is further subdivided into PPl, PP2A, PP2B, PP4, PPS and PP6 according to the sensitivity and specificity of the substrate to inhibitors or effectors (15,16). A number of extracellular stimuli affect the level of protein phosphorylation in the modulation of cell processes (17). These processes are involved in cellular proliferation, migration, growth, differentiation, metabolism, the immune system, cytoskeletal reorganization and muscle contraction (17). Over 50% of proteins in human cells are capable of undergoing reversible phosphorylation; Therefore, phosphorylation pathways exhibit promising potential applications in the treatment for a variety of different diseases (18).

The kidneys receive ~20% of cardiac output and consume 10% of the bodies oxygen to perform their main function of adjusting body-fluid constituents by glomerular filtration and renal tubular reabsorption (4). Each glomerulus consists of three main classes of cells forming the filtration layer: i) fenestrated-endothelium cells located inside the capillary, ii) mesangial cells located outside the capillary and iii) specialized epithelial cells called podocytes (19). Phosphotyrosine phosphatase is hyperactive in endothelial cells of the glomerular-mesangial-cell layer in human tissues (20). Furthermore, PTP serves a central role in podocyte homeostasis, and this has been demonstrated in a study in which treatment of podocytes with a nonspecific PTP inhibitor induced drastic morphological alterations in their actin-cytoskeleton network (21). Svennilson et al (22) demonstrated that the expression of PP1 and PP2A is ubiquitous in the early metanephric kidney. The importance of kinases in kidney disease is well established; However, the roles of phosphatases are yet to be fully elucidated (10). To the best of our knowledge, there has been little research on phosphatase in the kidneys. Accumulating evidence has indicated that phosphatases are involved in normal nephron growth and renal pathological processes, and may be a promising target for therapies in patients with renal diseases (10,23).

3. Features of PP2A

In eukaryotic cells, at least 99% of protein phosphorylation is associated with Ser/Thr residues (24). PP2A, which is one of the four major cytoplasmic Ser/Thr phosphatases, acts on a number of different components within various key signal-transduction pathways (25). The function and structure of PP2A is conserved in organisms ranging from yeasts to mammals, in which PP2A regulates many important cellular functions (26). The PP2A enzyme core is made up of a 65-kDa scaffolding subunit ‘A’, which modulates its enzymatic properties, and a 36-kDa catalytic subunit ‘C’ (27). These subunits bind to the regulatory subunit ‘B’ (PP2A-B) to form the various heterotrimeric complexes (28). The A and C subunits have two isoforms that are encoded by genes α and β (29). While these isoforms are strongly homologous for each other, the majority of cell types predominantly express the α isoform (29). There are four categories of the B subunit, including the PR55 (B), PR61 (B'), PR72/130 (B') and the striatin family (B'). The B subunit is contained in multiple isoforms (α up to ε) that are encoded by different genes. Because the structure of the B subunit varies dramatically, PP2A targets an extensive array of components involved in critical signal-transduction pathways that regulate cellular functions (29). Although the A and C subunits are widely expressed, the cellular localization and expression of the B subunit vary greatly across cell types and tissues (30-35).

PP2A dephosphorylates a number of key cellular molecules including Akt, MEK, MAPK, c-Myc, p53 and β-catenin (36). Furthermore, PP2A regulates a number of different cellular processes such as proliferation, metabolism and apoptosis (36). Aberrant PP2A regulation is commonly observed in a range of diseases such as cancer, cardiovascular pathologies and neurodegenerative disorders (29). Evidence has indicated that PP2A can act as a tumor suppressor (37). PP2A can suppress tumorigenesis via downregulation of the Akt/(TSC1/TSC1)/Rheb/mTOR signaling pathway, inactivation of c-Myc and antagonism of the Wnt/β-catenin pathway (38). Previous studies have also revealed that PP2A is essential in kidney organogenesis and developmental processes, and participates in kidney diseases via one of several complex mechanisms (39,40).

4. PP2A regulates ion-transport proteins and aquaporin-2 (AQP2)

Ion channels

The absorption of ions in the kidneys is regulated and controlled by multiple physiological mechanisms (41). Previous studies have indicated PP2A is responsible for the maintenance of ion channels and homeostasis (42-44). PP1 and PP2A serve an important role in the phosphorylation, surface distribution and function of Na+/Cl--dependent choline transporters (43). Ang II is an important regulator of the ouabain-resistant Na+-ATPase from renal proximal tubule cells, which are involved in the signal cascade of Ang II receptors, protein kinase (PK)A and PKC (42,44-46). Chronic malnutrition can stimulate the activity of renal tubulointerstitial Ang II and damage the regulation of phosphorylation that is mediated by PP2A (47). These events result in excessive reabsorption of Na+ in proximal renal tubuloepithelial cells (47). Gildea et al (48) demonstrated that PP2A mediates increased activity of Ang II, dopamine receptors and cAMP in proximal tubules. This aforementioned study also demonstrated that abnormal control of these systems leads to an increase in sodium reabsorption. Furthermore, cell-permeable second-messenger analogs cAMP and GMP can activate PP2A, which is important for plasma membrane recruitment of dopamine D1 receptor (D1R), angiotensin II type-2 receptor and inhibition of luminal Na+ transport (48). In human adenocarcinoma cells, PP2A also participates in stimulation of D1R, which increases Na+/K+-ATPase activity by accelerating Na+/K+-ATPase recruitment from intracellular pools into the basal-lateral membrane; Meanwhile, okadaic acid (OA), which a selective inhibitor of PP2A, inhibits the increase in Na+/K+-ATPase activity (49). Li et al (50) indicated that calyculin, which is a PP1 and PP2A inhibitor, inhibits Na+/K+-ATPase activity at a lower dose than that of OA in renal proximal tubules. In addition, potassium channels are also regulated by these phosphatases (51). 11,12-epoxyeicosatrienoic acid dilates preglomerular microvessels via adenosine A2A receptor mediation and activates conductance across the K+ channels in renal smooth muscles by stimulating PP2A (52). These findings revealed that PP2A functions cooperatively with this crucial regulatory mechanism in regulating the dynamics of Na+, K+ and Cl- flow (Fig. 1).


The targeting of AQP2 on the apical plasma membrane of renal collecting duct cells, which are used to maintain body water homeostasis in mammals, is mainly modulated via the activity of antidiuretic peptide arginine vasopressin (53). AQP2 protein has at least four vasopressin-regulated phosphorylation sites at serine residues 256, 261, 264 and 269 (54,55). Phosphorylation of these sites controls the transport of AQP2 in and out of the plasma membrane at the top of the collecting tube (56-60). PP1 and/or PP2A act on the internalization of membrane-associated AQP2 by reducing the phosphorylation of ser256 and ser264 in kidney inner-medullar tissue (Fig. 1). The phosphorylation site at serine-264 of AQP2 is also regulated by PP2B (61). However, PP2B does not affect the membrane accumulation of AQP2(61). Calyculin-mediated inhibition of PP2A activity leads to an increase in p256-AQP2 expression and a decrease in p261-AQP2 expression in MDCK-hAQP2 cells, which promotes AQP2 transport to the plasma membrane (62). Valenti et al (63) demonstrated that OA increases the phosphorylation of AQP2 at ser256 by 60% and promotes AQP2 to target the apical plasma membrane of collecting duct cells.

5. PP2A in renal development

PP2A serves a crucial role in embryonic development, and particularly in development and survival (40). Evidence has suggested that PP2A serves complicated stimulatory and inhibitory roles in growth- and hormone-factor signaling, especially in the extracellular signal-regulated ERK/MAPK cascade and in the activity of ubiquitous intermediary messengers during mitosis (64). PP2A appears to be involved in controlling the activity of maturation-promoting factor (MPF) (65,66) and the modulation of MAP-ERK kinase activity (67,68). Normal kidney development, beginning at embryonic day 12 (E12) in rats and during the 5th gestational week in humans, is strictly regulated and involves several crucial steps in order to achieve a predetermined number of functioning nephrons (39). On day 15 of embryonic development, the percentage of PP2A in total Ser/Thr phosphatase activity is 78% in rat kidneys, as evaluated using a phosphatase activity assay. At the El8 and E21 stages of nephrogenesis, the expression of PP2A is limited to the nephrogenic zone, in which it is strongly expressed (39). When nephrogenesis terminates, PP2A expression is downregulated substantially (39). Svennilson et al (22) demonstrated that PP2A mRNA is strongly expressed in various cell types during early development of the kidneys. Additionally, the use of low doses of OA inhibits early (E13) embryonic kidney growth and disturbs nephron formation in E15 kidneys. Subsequently, normal PP2A activity is indispensable to metanephric development, and inhibition of this activity can induce morphological disorder and apoptosis (22).

Recent studies have highlighted the particular importance of functional PP2A in Wnt signaling due to the fact Wnt-4 serves a key role in kidney development (69,70). Overall, these studies provide novel insights into the importance of PP2A activity during renal morphogenesis and within signal-transduction pathways.

6. PP2A and podocytes

Podocytes (or visceral epithelial cells) have complicated interdigitating foot processes (FPs) that cover the external surface of the glomerular basement membrane (71). Adjacent FPs from different units are interconnected by a continuous membrane structure called the slit diaphragm (19). The slit diaphragm consists of membrane and cytoskeletal proteins, such as synaptopodin, nephrin, podocin, α-actinin-4, podoplanin and CD2 Associated Protein, as well as signaling molecules, all of which serve important roles in maintaining the basic function of the glomerular filtration barrier (GFB) (72,73). Impairments in pathways and molecular processes that regulate the function of the GFB may lead to CKD (74). Congenital or acquired podocyte damage can cause podocytes to lose certain specific markers, causing disappearance of FPs, detachment and proteinuria (75). Additionally, podocyte injury is closely associated with a number of renal diseases, including diabetic nephropathy, membrane nephritis, IgA nephropathy and focal segmental glomerulosclerosis (75). Kumar and Tikoo (20) demonstrated that selective inhibition of PP2A activity to restore insulin levels can induce the phosphorylation of Sirtuin 1 and Forkhead Box O1 and increase the activity of AKT, causing degradation of p53 and podocyte death. Kobayashi et al (76) also indicated that utilizing OA to inhibit PP2A can suppress microtubule elongation and abolish process formation in conditionally immortalized mouse podocytes. Zhu et al (77) demonstrated that podocyte-specific knockout of PP2A (Pod-PP2A-KO) in mice causes considerable weight loss, growth retardation, proteinuria, severe lethargy, and mortality in >70% mice at 15 weeks of age. Histological examination has indicated severe glomerulopathy and dramatic loss of FPs, as well as reduced expression of a number of different slit-diaphragm molecules and impairment of cytoskeletal rearrangement in podocytes (77).

The highly conserved Y box protein 1 (YB-1) of the cold-shock protein family has been indicated to be associated with cellular stress response and renal fibrosis (78). YB-1 is a target molecule in PP2A dephosphorylation, and fine-tuning YB-1 via post-translational modification by modulating PP2A activity may serve a role in maintaining the functional integrity of podocytes and GFB (78). Zhong et al (79) revealed that podocyte-specific PP2A deficiency aggravates diabetic glomerulopathy and accelerates diabetic kidney disease. Arctigenin (ATG) is a major component of Fructus Arctii, a traditional herbal remedy that reduces proteinuria in patients with diabetes (79). ATG administration has been revealed to attenuate proteinuria and podocyte injury in mouse models of diabetes (79). Furthermore, enhanced PP2A activity occurring via ATG ameliorates podocyte adhesion partly through T335-mediated phosphorylation of drebrin-1 (DBN1). This aforementioned result reveals a novel mechanism in the regulation of podocyte cytoskeletal rearrangement (79). Selective inhibition of PP2A can improve insulin resistance, restore AKT levels, induce FOXO1 phosphorylation and rescue podocytes from cell death (20). These aforementioned data indicated that PP2A may be a potential drug target for the prevention of podocyte injury.

7. PP2A and renal carcinoma

Renal cell carcinoma (RCC) is one of the most common renal malignancies and accounts for ~2.4% of all cancers and 1.7% of total cancer-associated deaths worldwide (80). To date, therapeutics for patients with metastatic renal cancer remain limited in effectiveness and specificity (81). A number of human cancers are associated with PP2A dysfunction, such as lung cancer (82), breast cancer (83) and leukemia (84). Furthermore, downregulation of PP2A expression and its impact on cellular transformation reveals that PP2A can function as a tumor-suppressor gene in a number of different malignant cancers including leukemia, lung, breast, gastric and colon cancer (85). Increasing evidence has indicated that PP2A serves a tumor-suppressive role, but the individual roles of its subunits, which are deregulated in cancer, remain unknown (80). PP2A expression is decreased in RCC tissues, and patients with high expression of PP2A in tumor tissues exhibit improved survival compared with those exhibiting a low expression of PP2A (12). However, the mechanism of PP2A deregulation in RCC is yet to be determined. Evidence has suggested that PP2A inactivation in cancer mainly occurs via overexpression of suvar/enhancer of zeste/trithorax and cancerous inhibitor of PP2A, which are both endogenous PP2A inhibitors (86-89).

MicroRNAs (miRNA/miR) can act as oncogenes or tumor suppressor genes, depending on the function of target genes in malignant tumors (87). Additionally, miR-183 (a member of the miR-183-96-182 cluster) is expressed at higher levels in two renal cancer cell lines (ACHN and A498) and can promote the growth of renal cancer cells (87). A study has indicated that miR-183 can directly target the 3'untranslated regions of PP2A-Cα, PP2A-Cβ mRNA, as well as PP2A-B56-γ protein phosphatase subunits and inhibit their expression (81). These results confirm that miR-183 serves an oncogenic role in renal cancer cells by targeting PP2A directly (81). PP2A, Akt and Mcl-1 are essential in RCC malignancy and treatment resistance (90). The PP2A/Akt axis is an important substitute for aspirin-mediated induction of susceptibility to ABT-737 mediated-apoptosis in RCC cells (90). Styryllactone (R)-goniothalamin and its enantiomer (S)-goniothalamin cause apoptosis in cancer cells of human kidneys by reducing Ras expression and PP2A activity (91).

In human renal-carcinoma Caki cells, downregulation of PP2A via small-interfering RNA can significantly inhibit the upregulation of a pro-apoptotic protein Bim via the pharmacological inhibitor ZFL [cathepsin S inhibitor: Z-FL-COCHO (ZFL)] (92). Downregulation of PP2A decreases apoptosis and cleavage of poly (ADP-ribose) polymerase in ZFL- and oxaliplatin-treated Caki cells (92). Combined treatment with Raf inhibitors sorafenib and GW5074 is used to produce a two-pronged attack on renal cancer cells (93). The two inhibitors promote translocation of pC-RafS338 and pDAPKS308 from mitochondria to cytoplasm, resulting in mitochondrial dysfunction and ROS generation. Subsequently, reactive oxygen species (ROS) accelerate the PP2A-mediated dephosphorylation of pDAPKS308 to DAPK. Finally, PP2A separates from the C-Raf-DAPK complex and leads to cancer cell death (93). Luteolin also induces apoptosis in 786-o cells (94). This cytotoxicity is caused by the downregulation of Akt and consequent upregulation of Ask1, p38 and JNK activity, which is regulated by PP2A activation (94).

In summary, PP2A expression may be a useful tool that can be used in the prediction of prognosis and therapeutic outcome in patients with RCC. Further research on the molecular mechanisms of PP2A in human RCC will facilitate the identification of novel therapeutics and the development of effective treatments for patients with renal cancer.

8. PP2A in CKD

Glomerulosclerosis and tubulointerstitial fibrosis are the major pathological features of renal fibrosis, which is the final manifestation of a number of different CKDs (95). As conductors, renal microvascular endothelial cells (EC) serve important roles in kidney fibrosis (96). The association between renal fibrosis and endothelial dysfunction is well established (97). Endothelial dysfunction leads to a significant reduction in the number of peritubular capillaries in the interstitium (97). Chronic ischemia and hypoxia result in scar formation and remodeling processes in renal tissues (98). A previous study has indicated that Tyr nitration in the C subunit of PP2A decreases PP2Ac tyrosine phosphorylation and increases PP2A activity and endothelial dysfunction (99). TGF-β1-induced nitrification accelerates the nitrification of PP2Ac and increases the activity of PP2A in endothelial cells (10). Okadaic acid inhibits the activity of PP2A, weakening the effects of PP2A on EC cytoskeletal rearrangement induced by thrombin or nocodazole (100). This finding indicates that PP2A activity serves an important role in the maintenance of the EC cytoskeleton. Endothelial-mesenchymal transition (EndMT) is a major cellular behavioral mechanism that aims to increase the production of myofibroblasts (101), which are involved in the pathogenesis and progression of renal fibrosis (102-105). Furthermore, EndMT serves a key role in the development of CKD (106,107).

PP2A activation occurs in mouse unilateral ureteral obstruction and TGF-β1-treated human umbilical vein endothelial cells (HUVECs) in vitro (10). Additionally, OA significantly inhibits the expression of α-smooth muscle actin (a fibroblast marker), which is induced by TGF-β1 and maintains the expression of VE cadherin in HUVECs (10). Furthermore, TGF-β1 decreases the abundance of phosphorylated serine and threonine residues in occludin immunoprecipitates, which is significantly inhibited by pretreatment with OA (10). Erythrocyte sphingosine 1-phosphate serves a beneficial role in CKD by promoting the activity of 2,3-BPG (an erythrocyte-specific metabolite that negatively regulates the binding affinity of hemoglobin-O2) and subsequently triggering O2 delivery to renal cells and tissues (108). These events counteract hypoxia-induced kidney damage and slow CKD progression by inhibiting PP2A activity (108). PP2Ac serves an important role in the dephosphorylation activity of PP2A (25), and it has been demonstrated that inhibition of PP2Ac by OA attenuates renal fibrosis by suppressing fibronectin and collagen I expression (109). These events reverse epithelial-mesenchymal transition in renal tubules, while ectopic overexpression of PP2Ac accelerates tubular extracellular matrix (ECM) accumulation in vitro (109) (Fig. 2). Additionally, nitration of the PP2Ac tyrosine is crucial for PP2A activation during EndMT (10). Wu and Wilson (99) suggested that microvascular endothelial cells produce peroxynitrite, which nitrates PP2Ac under proinflammatory stimuli. This nitration enhances the activity of PP2A in the mediation of endothelial barrier dysfunction. Inhibition of NO and O2 production by NG-nitro-L-arginine methyl ester (an inhibitor of NO synthetases) and apocynin (APO, a specific inhibitor of NADPH oxidase) decreases the nitrification of PP2Ac and suppresses the process of EndMT via induction of TGF-β1 activity (99). Furthermore, tyrosine 127 (Tyr127) is essential for PP2Ac nitration, while inhibiting PP2Ac Tyr127 nitration with the peptide TAT-Y127WT effectively decreases PP2Ac nitration and ameliorates ECM deposition and capillary rarefaction (Fig. 2) (110). These results indicate that PP2Ac may be a novel drug target that could be used in anti-fibrotic therapies.

CKD is not only the main risk factor in acute myocardial infarction (AMI) but also an important factor in the reduced survival rate of patients with AMI (111-113). CKD downregulates PP2A-B55α protein expression, resulting in upregulated Akt-Thr308 phosphorylation (114). Decreased Akt activation, which is impaired by insufficient phosphorylation of ser473 during reperfusion, contributes to enlargement of myocardial infarct foci (114). These results indicate that PP2A activates the process of EndMT, while blocking PP2A signaling can inhibit this process. Therefore, inhibition of PP2A activity to prevent endothelial-mesenchymal transition is a promising strategy that could be used in anti-CKD therapies.

9. PP2A in renal inflammation

Inflammation, which is the process of detecting and eliminating harmful pathogens, is the main pathogenic mechanism of CKD and AKI (115). PP2A has been identified as an effective negative regulator of a number of different inflammatory signaling pathways (116,117), including dephosphorylation and inhibition of p65 NF-κB (118,119). An increase in PP2A activity by ATG attenuates the effects of NF-κB-mediated inflammation and enhances the stability of podocyte actin cytoskeleton via DBN1 dephosphorylation (79). The renal dopaminergic system is involved in the regulation of ROS production and the inflammatory response (120-125). A previous study indicated that dopamine D2 receptor (D2R) controls inflammation in the kidneys by modulating Akt dephosphorylation via PP2A (126). The increased PP2A activity inhibits increases in NF-κB activity, which are induced by D2R silencing (126). PP2A is also a major cellular phosphatase that can potentially contribute to NF-κB activity (127). In these events, PP2A regulates at least three different pathways, including TNF receptor-associated factor 2, IKK and NF-κB p65 during the downregulation of NF-κB activity (128). Inactivation of PP2A via a PTK/PTP imbalance triggered by oxidative stress, causes NF-κB activation, which contributes to the accumulation of oxidative stress in aged rat kidneys (11). Inactivation or knockdown of PP2A triggers activation of NF-κB signaling components, such as NIK/IKK and MAPKs (ERK, p38, and JNK), leading to NF-κB activation (11). PP2A is also a negative regulator of TGF-β1-activated kinase 1 activation in cultured mesangial cells (129). Studies on senescence marker protein-30 (SMP30) have indicated that blocking the inactivation of PP1 and PP2A via oxidative stress leads to the activation of NF-κB in the kidneys of SMP30Y/-mice (130). Therefore, PP2A regulation of NF-κB activity may provide a novel therapeutic target for the development of anti-inflammatory therapies in patients with kidney disease. Fig. 3 illustrates how PP2A regulates NF-κB by participating in a range of cellular and molecular mechanisms involved in renal inflammation.

10. Discussion

The current understanding of the structure and function of PP2A is extensive, and links between PP2A and renal diseases are becoming increasingly clear. PP2A serves diverse roles in renal pathophysiology, and normal PP2A activity is required for regulating ion channels to maintain the homeostasis of Na+, K+ and Cl- (49). PP2A also regulates the phosphorylation of AQP2 and its membrane accumulations to adjust urine concentration (63). Normal PP2A activity is critical not only in the formation and function of podocytes (21) but also in renal morphogenesis and development (40). It should be noted that patients with RCC who exhibit a higher PP2A expression have a higher chance of survival (12). PP2A expression may be useful in predicting patient prognosis and therapeutic outcomes in patients with RCC. PP2A has also been identified to be an antifibrotic factor and may be a promising therapeutic target in the treatment of renal fibrosis (23). In renal inflammation, PP2A is associated with a number of signaling pathways that regulate NF-κB activity (11,40,118,128). As PP2A serves numerous versatile roles in the pathogenic progression of kidney diseases, targeting PP2A in future therapeutics may improve patient outcomes. However, future studies should further examine the mechanisms of PP2A in the progression of kidney diseases.


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Authors' contributions

SW, JW and LY were involved in study conception and interpretation, writing and critically revising the manuscript. LS, YM and ZH wrote the manuscript. QF was involved with conception and design of the figures. All authors read and approved the final manuscript.

Ethics approval and consent to participate

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Patient consent for publication

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Competing interests

The authors declare that they have no competing interests.



Klein J and Schanstra JP: Implementation of proteomics biomarkers in nephrology: From animal models to human application? Proteomics Clin Appl. 13(e1800089)2019.PubMed/NCBI View Article : Google Scholar


Ferenbach DA and Bonventre JV: Acute kidney injury and chronic kidney disease: From the laboratory to the clinic. Nephrol Ther. 12 (Suppl 1):S41–S48. 2016.PubMed/NCBI View Article : Google Scholar


Ferenbach DA and Bonventre JV: Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol. 11:264–276. 2015.PubMed/NCBI View Article : Google Scholar


Eirin A, Lerman A and Lerman LO: The emerging role of mitochondrial targeting in kidney disease. Handb Exp Pharmacol. 240:229–250. 2017.PubMed/NCBI View Article : Google Scholar


Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY and Yang CW: Chronic kidney disease: Global dimension and perspectives. Lancet. 382:260–272. 2013.PubMed/NCBI View Article : Google Scholar


Chertow GM, Burdick E, Honour M, Bonventre JV and Bates DW: Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol. 16:3365–3370. 2005.PubMed/NCBI View Article : Google Scholar


Mumby MC and Walter G: Protein serine/threonine phosphatases: Structure, regulation, and functions in cell growth. Physiol Rev. 73:673–699. 1993.PubMed/NCBI View Article : Google Scholar


Eichhorn PJ, Creyghton MP and Bernards R: Protein phosphatase 2A regulatory subunits and cancer. Biochim Biophys Acta. 1795:1–15. 2009.PubMed/NCBI View Article : Google Scholar


Tsao CC, Nica AF, Kurinna SM, Jiffar T, Mumby M and Ruvolo PP: Mitochondrial protein phosphatase 2A regulates cell death induced by simulated ischemia in kidney NRK-52E cells. Cell Cycle. 6:2377–2385. 2007.PubMed/NCBI View Article : Google Scholar


Deng Y, Guo Y, Liu P, Zeng R, Ning Y, Pei G, Li Y, Chen M, Guo S, Li X, et al: Blocking protein phosphatase 2A signaling prevents endothelial-to-mesenchymal transition and renal fibrosis: A peptide-based drug therapy. Sci Rep. 6(19821)2016.PubMed/NCBI View Article : Google Scholar


Jin Jung K, Hyun Kim D, Kyeong Lee E, Woo Song C, Pal Yu B and Young Chung H: Oxidative stress induces inactivation of protein phosphatase 2A, promoting proinflammatory NF-kappaB in aged rat kidney. Free Radic Biol Med. 61:206–217. 2013.PubMed/NCBI View Article : Google Scholar


Li J, Sheng C, Li W and Zheng JH: Protein phosphatase-2A is down-regulated in patients within clear cell renal cell carcinoma. Int J Clin Exp Pathol. 7:1147–1153. 2014.PubMed/NCBI


Sen CK: Cellular thiols and redox-regulated signal transduction. Curr Top Cell Regul. 36:1–30. 2000.PubMed/NCBI View Article : Google Scholar


Barik S: Protein phosphorylation and signal transduction. Subcell Biochem. 26:115–164. 1996.PubMed/NCBI View Article : Google Scholar


Shi Y: Serine/threonine phosphatases: Mechanism through structure. Cell. 139:468–484. 2009.PubMed/NCBI View Article : Google Scholar


Barford D, Das AK and Egloff MP: The structure and mechanism of protein phosphatases: Insights into catalysis and regulation. Annu Rev Biophys Biomol Struct. 27:133–164. 1998.PubMed/NCBI View Article : Google Scholar


Barford D: Colworth medal lecture. Structural studies of reversible protein phosphorylation and protein phosphatases. Biochem Soc Trans. 27:751–766. 1999.PubMed/NCBI View Article : Google Scholar


Hornbeck PV, Kornhauser JM, Tkachev S, Zhang B, Skrzypek E, Murray B, Latham V and Sullivan M: PhosphoSitePlus: A comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res. 40:D261–D270. 2012.PubMed/NCBI View Article : Google Scholar


Geraldes P: Protein phosphatases and podocyte function. Curr Opin Nephrol Hypertens. 27:49–55. 2018.PubMed/NCBI View Article : Google Scholar


Kumar S and Tikoo K: Independent role of PP2A and mTORc1 in palmitate induced podocyte death. Biochimie. 112:73–84. 2015.PubMed/NCBI View Article : Google Scholar


Reiser J, Pixley FJ, Hug A, Kriz W, Smoyer WE, Stanley ER and Mundel P: Regulation of mouse podocyte process dynamics by protein tyrosine phosphatases rapid communication. Kidney Int. 57:2035–2042. 2000.PubMed/NCBI View Article : Google Scholar


Svennilson J, Durbeej M, Celsi G, Laestadius A, da Cruz e Silva EF, Ekblom P and Aperia A: Evidence for a role of protein phosphatases 1 and 2A during early nephrogenesis. Kidney Int. 48:103–110. 1995.PubMed/NCBI View Article : Google Scholar


Everett AD, Xue C and Stoops T: Developmental expression of protein phosphatase 2A in the kidney. J Am Soc Nephrol. 10:1737–1745. 1999.PubMed/NCBI View Article : Google Scholar


Gotz J, Probst A, Mistl C, Nitsch RM and Ehler E: Distinct role of protein phosphatase 2A subunit Calpha in the regulation of E-cadherin and beta-catenin during development. Mech Dev. 93:83–93. 2000.PubMed/NCBI View Article : Google Scholar


Mumby M: The 3D structure of protein phosphatase 2A: New insights into a ubiquitous regulator of cell signaling. ACS Chem Biol. 2:99–103. 2007.PubMed/NCBI View Article : Google Scholar


Janssens V and Goris J: Protein phosphatase 2A: A highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J. 353:417–439. 2001.PubMed/NCBI View Article : Google Scholar


Turowski P, Favre B, Campbell KS, Lamb NJ and Hemmings BA: Modulation of the enzymatic properties of protein phosphatase 2A catalytic subunit by the recombinant 65-kDa regulatory subunit PR65alpha. Eur J Biochem. 248:200–208. 1997.PubMed/NCBI View Article : Google Scholar


Sontag E: Protein phosphatase 2A: The Trojan horse of cellular signaling. Cell Signal. 13:7–16. 2001.PubMed/NCBI View Article : Google Scholar


O'Connor CM, Perl A, Leonard D, Sangodkar J and Narla G: Therapeutic targeting of PP2A. Int J Biochem Cell Biol. 96:182–193. 2018.PubMed/NCBI View Article : Google Scholar


Forester CM, Maddox J, Louis JV, Goris J and Virshup DM: Control of mitotic exit by PP2A regulation of Cdc25C and Cdk1. Proc Natl Acad Sci USA. 104:19867–19872. 2007.PubMed/NCBI View Article : Google Scholar


Slupe AM, Merrill RA and Strack S: Determinants for substrate specificity of protein phosphatase 2A. Enzyme Res. 2011(398751)2011.PubMed/NCBI View Article : Google Scholar


Flegg CP, Sharma M, Medina-Palazon C, Jamieson C, Galea M, Brocardo MG, Mills K and Henderson BR: Nuclear export and centrosome targeting of the protein phosphatase 2A subunit B56alpha: Role of B56alpha in nuclear export of the catalytic subunit. J Biol Chem. 285:18144–18154. 2010.PubMed/NCBI View Article : Google Scholar


Bononi A, Agnoletto C, De Marchi E, Marchi S, Patergnani S, Bonora M, Giorgi C, Missiroli S, Poletti F, Rimessi A and Pinton P: Protein kinases and phosphatases in the control of cell fate. Enzyme Res. 2011(329098)2011.PubMed/NCBI View Article : Google Scholar


Riedel CG, Katis VL, Katou Y, Mori S, Itoh T, Helmhart W, Gálová M, Petronczki M, Gregan J and Cetin B: Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I. Nature. 441:53–61. 2006.PubMed/NCBI View Article : Google Scholar


Jin Z, Shi J, Saraf A, Mei W, Zhu GZ, Strack S and Yang J: The 48-kDa alternative translation isoform of PP2A:B56epsilon is required for Wnt signaling during midbrain-hindbrain boundary formation. J Biol Chem. 284:7190–7200. 2009.PubMed/NCBI View Article : Google Scholar


Seshacharyulu P, Pandey P, Datta K and Batra SK: Phosphatase: PP2A structural importance, regulation and its aberrant expression in cancer. Cancer Lett. 335:9–18. 2013.PubMed/NCBI View Article : Google Scholar


Kanno T, Tsuchiya A, Shimizu T, Nakao S, Tanaka A and Nishizaki T: Effects of newly synthesized DCP-LA-phospholipids on protein kinase C and protein phosphatases. Cell Physiol Biochem. 31:555–564. 2013.PubMed/NCBI View Article : Google Scholar


Kurimchak A and Grana X: PP2A counterbalances phosphorylation of pRB and mitotic proteins by multiple CDKs: Potential implications for PP2A disruption in cancer. Genes Cancer. 3:739–748. 2012.PubMed/NCBI View Article : Google Scholar


Svennilson J, Sandberg-Nordqvist A and Aperia A: Age-dependent expression of protein phosphatase 2A in the developing rat kidney. Pediatr Nephrol. 13:800–805. 1999.PubMed/NCBI View Article : Google Scholar


Yang J, Wu J, Tan C and Klein PS: PP2A:B56epsilon is required for Wnt/beta-catenin signaling during embryonic development. Development. 130:5569–5578. 2003.PubMed/NCBI View Article : Google Scholar


Jørgensen PL: Sodium and potassium ion pump in kidney tubules. Physiol Rev. 60:864–917. 1980.PubMed/NCBI View Article : Google Scholar


Rangel LB, Lopes AG, Lara LS, Carvalho TL, Silva IV, Oliveira MM, Einicker-Lamas M, Vieyra A, Nogaroli L and Caruso-Neves C: PI-PLCbeta is involved in the modulation of the proximal tubule Na+-ATPase by angiotensin II. Regul Pept. 127:177–182. 2005.PubMed/NCBI View Article : Google Scholar


Gates J Jr, Ferguson SM, Blakely RD and Apparsundaram S: Regulation of choline transporter surface expression and phosphorylation by protein kinase C and protein phosphatase 1/2A. J Pharmacol Exp Ther. 310:536–545. 2004.PubMed/NCBI View Article : Google Scholar


Vieira-Filho LD, Cabral EV, Farias JS, Silva PA, Muzi-Filho H, Vieyra A and Paixão AD: Renal molecular mechanisms underlying altered Na+ handling and genesis of hypertension during adulthood in prenatally undernourished rats. Br J Nutr. 111:1932–1944. 2014.PubMed/NCBI View Article : Google Scholar


Dias J, Ferrao FM, Axelband F, Carmona AK, Lara LS and Vieyra A: ANG-(3-4) inhibits renal Na+-ATPase in hypertensive rats through a mechanism that involves dissociation of ANG II receptors, heterodimers, and PKA. Am J Physiol Renal Physiol. 306:F855–F863. 2014.PubMed/NCBI View Article : Google Scholar


Vieira-Filho LD, Lara LS, Silva PA, Santos FT, Luzardo R, Oliveira FS, Paixão AD and Vieyra A: Placental malnutrition changes the regulatory network of renal Na-ATPase in adult rat progeny: Reprogramming by maternal α-tocopherol during lactation. Arch Biochem Biophys. 505:91–97. 2011.PubMed/NCBI View Article : Google Scholar


Silva PA, Muzi-Filho H, Pereira-Acacio A, Dias J, Martins JF, Landim-Vieira M, Verdoorn KS, Lara LS, Vieira-Filho LD, Cabral EV, et al: Altered signaling pathways linked to angiotensin II underpin the upregulation of renal Na(+)-ATPase in chronically undernourished rats. Biochim Biophys Acta. 1842:2357–2366. 2014.PubMed/NCBI View Article : Google Scholar


Gildea JJ, Xu P, Kemp BA, Carey RM, Jose PA and Felder RA: The dopamine D1 receptor and angiotensin II type-2 receptor are required for inhibition of sodium transport through a protein phosphatase 2A pathway. Hypertension. 73:1258–1265. 2019.PubMed/NCBI View Article : Google Scholar


Lecuona E, Garcia A and Sznajder JI: A novel role for protein phosphatase 2A in the dopaminergic regulation of Na, K-ATPase. FEBS Lett. 481:217–220. 2000.PubMed/NCBI View Article : Google Scholar


Li D, Cheng SX, Fisone G, Caplan MJ, Ohtomo Y and Aperia A: Effects of okadaic acid, calyculin A, and PDBu on state of phosphorylation of rat renal Na+-K+-ATPase. Am J Physiol. 275:F863–F869. 1998.PubMed/NCBI View Article : Google Scholar


Tiran Z, Peretz A, Sines T, Shinder V, Sap J, Attali B and Elson A: Tyrosine phosphatases epsilon and alpha perform specific and overlapping functions in regulation of voltage-gated potassium channels in Schwann cells. Mol Biol Cell. 17:4330–4342. 2006.PubMed/NCBI View Article : Google Scholar


Capdevila J and Wang W: Role of cytochrome P450 epoxygenase in regulating renal membrane transport and hypertension. Curr Opin Nephrol Hypertens. 22:163–169. 2013.PubMed/NCBI View Article : Google Scholar


Nielsen S and Agre P: The aquaporin family of water channels in kidney. Kidney Int. 48:1057–1068. 1995.PubMed/NCBI View Article : Google Scholar


Christensen BM, Zelenina M, Aperia A and Nielsen S: Localization and regulation of PKA-phosphorylated AQP2 in response to V(2)-receptor agonist/antagonist treatment. Am J Physiol Renal Physiol. 278:F29–F42. 2000.PubMed/NCBI View Article : Google Scholar


Hoffert JD, Pisitkun T, Wang G, Shen RF and Knepper MA: Quantitative phosphoproteomics of vasopressin-sensitive renal cells: Regulation of aquaporin-2 phosphorylation at two sites. Proc Natl Acad Sci USA. 103:7159–7164. 2006.PubMed/NCBI View Article : Google Scholar


Tamma G, Robben JH, Trimpert C, Boone M and Deen PM: Regulation of AQP2 localization by S256 and S261 phosphorylation and ubiquitination. Am J Physiol Cell Physiol. 300:C636–C646. 2011.PubMed/NCBI View Article : Google Scholar


Moeller HB, Knepper MA and Fenton RA: Serine 269 phosphorylated aquaporin-2 is targeted to the apical membrane of collecting duct principal cells. Kidney Int. 75:295–303. 2009.PubMed/NCBI View Article : Google Scholar


Brown D: The ins and outs of aquaporin-2 trafficking. Am J Physiol Renal Physiol. 284:F893–F901. 2003.PubMed/NCBI View Article : Google Scholar


Kamsteeg EJ, Heijnen I, van Os CH and Deen PM: The subcellular localization of an aquaporin-2 tetramer depends on the stoichiometry of phosphorylated and nonphosphorylated monomers. J Cell Biol. 151:919–930. 2000.PubMed/NCBI View Article : Google Scholar


Hoffert JD, Fenton RA, Moeller HB, Simons B, Tchapyjnikov D, McDill BW, Yu MJ, Pisitkun T, Chen F and Knepper MA: Vasopressin-stimulated increase in phosphorylation at Ser269 potentiates plasma membrane retention of aquaporin-2. J Biol Chem. 283:24617–24627. 2008.PubMed/NCBI View Article : Google Scholar


Ren H, Yang B, Ruiz JA, Efe O, Ilori TO, Sands JM and Klein JD: Phosphatase inhibition increases AQP2 accumulation in the rat IMCD apical plasma membrane. Am J Physiol Renal Physiol. 311:F1189–F1197. 2016.PubMed/NCBI View Article : Google Scholar


Tamma G, Lasorsa D, Trimpert C, Ranieri M, Di Mise A, Mola MG, Mastrofrancesco L, Devuyst O, Svelto M, Deen PM and Valenti G: A protein kinase A-independent pathway controlling aquaporin 2 trafficking as a possible cause for the syndrome of inappropriate antidiuresis associated with polycystic kidney disease 1 haploinsufficiency. J Am Soc Nephrol. 25:2241–2253. 2014.PubMed/NCBI View Article : Google Scholar


Valenti G, Procino G, Carmosino M, Frigeri A, Mannucci R, Nicoletti I and Svelto M: The phosphatase inhibitor okadaic acid induces AQP2 translocation independently from AQP2 phosphorylation in renal collecting duct cells. J Cell Sci. 113:1985–1992. 2000.PubMed/NCBI


Millward TA, Zolnierowicz S and Hemmings BA: Regulation of protein kinase cascades by protein phosphatase 2A. Trends Biochem Sci. 24:186–191. 1999.PubMed/NCBI View Article : Google Scholar


Lee TH, Solomon MJ, Mumby MC and Kirschner MW: INH, a negative regulator of MPF, is a form of protein phosphatase 2A. Cell. 64:415–423. 1991.PubMed/NCBI View Article : Google Scholar


Izumi T, Walker DH and Maller JL: Periodic changes in phosphorylation of the Xenopus cdc25 phosphatase regulate its activity. Mol Biol Cell. 3:927–939. 1992.PubMed/NCBI View Article : Google Scholar


Haystead TA, Weiel JE, Litchfield DW, Tsukitani Y, Fischer EH and Krebs EG: Okadaic acid mimics the action of insulin in stimulating protein kinase activity in isolated adipocytes. The role of protein phosphatase 2a in attenuation of the signal. J Biol Chem. 265:16571–16580. 1990.PubMed/NCBI


Tsao H and Greene LA: The roles of macromolecular synthesis and phosphorylation in the regulation of a protein kinase activity transiently stimulated by nerve growth factor. J Biol Chem. 266:12981–12988. 1991.PubMed/NCBI


Stark K, Vainio S, Vassileva G and McMahon AP: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature. 372:679–683. 1994.PubMed/NCBI View Article : Google Scholar


Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL III, Lee JJ, Tilghman SM, Gumbiner BM and Costantini F: The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell. 90:181–192. 1997.PubMed/NCBI View Article : Google Scholar


Altintas MM and Reiser J: Bridges to cross, burn, and mend: Cells of renin lineage as podocyte progenitors. Am J Physiol Renal Physiol. 309:F499–F500. 2015.PubMed/NCBI View Article : Google Scholar


Pagtalunan ME, Miller PL, Jumping-Eagle S, Nelson RG, Myers BD, Rennke HG, Coplon NS, Sun L and Meyer TW: Podocyte loss and progressive glomerular injury in type II diabetes. J Clin Invest. 99:342–348. 1997.PubMed/NCBI View Article : Google Scholar


Huber TB and Benzing T: The slit diaphragm: A signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 14:211–216. 2005.PubMed/NCBI View Article : Google Scholar


Sedor JR, Madhavan SM, Kim JH and Konieczkowski M: Out on a LIM: Chronic kidney disease, podocyte phenotype and the Wilm's tumor interacting protein (WTIP). Trans Am Clin Climatol Assoc. 122:184–197. 2011.PubMed/NCBI


Liu M, Liang K, Zhen J, Zhou M, Wang X, Wang Z, Wei X, Zhang Y, Sun Y, Zhou Z, et al: Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling. Nat Commun. 8(413)2017.PubMed/NCBI View Article : Google Scholar


Kobayashi N, Reiser J, Schwarz K, Sakai T, Kriz W and Mundel P: Process formation of podocytes: Morphogenetic activity of microtubules and regulation by protein serine/threonine phosphatase PP2A. Histochem Cell Biol. 115:255–266. 2001.PubMed/NCBI View Article : Google Scholar


Zhu X, Ye Y, Xu C, Gao C, Zhang Y, Zhou J, Lin W and Mao J: Protein phosphatase 2A modulates podocyte maturation and glomerular functional integrity in mice. Cell Commun Signal. 17(91)2019.PubMed/NCBI View Article : Google Scholar


Hanssen L, Frye BC, Ostendorf T, Alidousty C, Djudjaj S, Boor P, Rauen T, Floege J, Mertens PR and Raffetseder U: Y-box binding protein-1 mediates profibrotic effects of calcineurin inhibitors in the kidney. J Immunol. 187:298–308. 2011.PubMed/NCBI View Article : Google Scholar


Zhong Y, Lee K, Deng Y, Ma Y, Chen Y, Li X, Wei C, Yang S, Wang T, Wong NJ, et al: Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes. Nat Commun. 10(4523)2019.PubMed/NCBI View Article : Google Scholar


Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015.PubMed/NCBI View Article : Google Scholar


Qiu M, Liu L, Chen L, Tan G, Liang Z, Wang K, Liu J and Chen H: MicroRNA-183 plays as oncogenes by increasing cell proliferation, migration and invasion via targeting protein phosphatase 2A in renal cancer cells. Biochem Biophys Res Commun. 452:163–169. 2014.PubMed/NCBI View Article : Google Scholar


Liu P, Xiang Y, Liu X, Zhang T, Yang R, Chen S, Xu L, Yu Q, Zhao H, Zhang L, et al: Cucurbitacin B induces the lysosomal degradation of EGFR and suppresses the CIP2A/PP2A/Akt signaling axis in gefitinib-resistant non-small cell lung cancer. Molecules. 24(647)2019.PubMed/NCBI View Article : Google Scholar


Cairns J, Ly RC, Niu N, Kalari KR, Carlson EE and Wang L: CDC25B partners with PP2A to induce AMPK activation and tumor suppression in triple negative breast cancer. NAR Cancer. 2(zcaa39)2020.PubMed/NCBI View Article : Google Scholar


Vicente C, Arriazu E, Martínez-Balsalobre E, Peris I, Marcotegui N, García-Ramírez P, Pippa R, Rabal O, Oyarzábal J, Guruceaga E, et al: A novel FTY720 analogue targets SET-PP2A interaction and inhibits growth of acute myeloid leukemia cells without inducing cardiac toxicity. Cancer Lett. 468:1–13. 2020.PubMed/NCBI View Article : Google Scholar


Westermarck J and Hahn WC: Multiple pathways regulated by the tumor suppressor PP2A in transformation. Trends Mol Med. 14:152–160. 2008.PubMed/NCBI View Article : Google Scholar


Xing ML, Lu YF, Wang DF, Zou XY, Zhang SX and Yun Z: Clinical significance of sCIP2A levels in breast cancer. Eur Rev Med Pharmacol Sci. 20:82–91. 2016.PubMed/NCBI


Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M and Croce CM: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:2999–3004. 2004.PubMed/NCBI View Article : Google Scholar


Kauko O and Westermarck J: Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer. Int J Biochem Cell Biol. 96:157–164. 2018.PubMed/NCBI View Article : Google Scholar


Lambrecht C, Haesen D, Sents W, Ivanova E and Janssens V: Structure, regulation, and pharmacological modulation of PP2A phosphatases. Methods Mol Biol. 1053:283–305. 2013.PubMed/NCBI View Article : Google Scholar


Ou YC, Li JR, Wang JD, Chen WY, Kuan YH, Yang CP, Liao SL, Lu HC and Chen CJ: Aspirin restores ABT-737-mediated apoptosis in human renal carcinoma cells. Biochem Biophys Res Commun. 502:187–193. 2018.PubMed/NCBI View Article : Google Scholar


de Fatima A, Zambuzzi WF, Modolo LV, Tarsitano CA, Gadelha FR, Hyslop S, de Carvalho JE, Salgado I, Ferreira CV and Pilli RA: Cytotoxicity of goniothalamin enantiomers in renal cancer cells: Involvement of nitric oxide, apoptosis and autophagy. Chem Biol Interact. 176:143–150. 2008.PubMed/NCBI View Article : Google Scholar


Seo SU, Woo SM, Min KJ and Kwon TK: Z-FL-COCHO, a cathepsin S inhibitor, enhances oxaliplatin-induced apoptosis through upregulation of Bim expression. Biochem Biophys Res Commun. 498:849–854. 2018.PubMed/NCBI View Article : Google Scholar


Tsai YT, Chuang MJ, Tang SH, Wu ST, Chen YC, Sun GH, Hsiao PW, Huang SM, Lee HJ, Yu CP, et al: Novel cancer therapeutics with allosteric modulation of the mitochondrial C-Raf-DAPK complex by raf inhibitor combination therapy. Cancer Res. 75:3568–3582. 2015.PubMed/NCBI View Article : Google Scholar


Ou YC, Kuan YH, Li JR, Raung SL, Wang CC, Hung YY and Chen CJ: Induction of apoptosis by luteolin involving akt inactivation in human 786-o renal cell carcinoma cells. Evid Based Complement Alternat Med. 2013(109105)2013.PubMed/NCBI View Article : Google Scholar


Liu Y: Renal fibrosis: New insights into the pathogenesis and therapeutics. Kidney Int. 69:213–217. 2006.PubMed/NCBI View Article : Google Scholar


Daehn I and Bottinger EP: Microvascular endothelial cells poised to take center stage in experimental renal fibrosis. J Am Soc Nephrol. 26:767–769. 2015.PubMed/NCBI View Article : Google Scholar


Bohle A, Mackensen-Haen S and Wehrmann M: Significance of postglomerular capillaries in the pathogenesis of chronic renal failure. Kidney Blood Press Res. 19:191–195. 1996.PubMed/NCBI View Article : Google Scholar


Fine LG, Orphanides C and Norman JT: Progressive renal disease: The chronic hypoxia hypothesis. Kidney Int Suppl. 65 (Suppl):S74–S78. 1998.PubMed/NCBI


Wu F and Wilson JX: Peroxynitrite-dependent activation of protein phosphatase type 2A mediates microvascular endothelial barrier dysfunction. Cardiovasc Res. 81:38–45. 2009.PubMed/NCBI View Article : Google Scholar


Kása A, Czikora I, Verin AD, Gergely P and Csortos C: Protein phosphatase 2A activity is required for functional adherent junctions in endothelial cells. Microvasc Res. 89:86–94. 2013.PubMed/NCBI View Article : Google Scholar


Kriz W, Kaissling B and Le Hir M: Epithelial-mesenchymal transition (EMT) in kidney fibrosis: Fact or fantasy? J Clin Invest. 121:468–474. 2011.PubMed/NCBI View Article : Google Scholar


Lipphardt M, Dihazi H, Jeon NL, Dadafarin S, Ratliff BB, Rowe DW, Müller GA and Goligorsky MS: Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial-mesenchymal transition. Nephrol Dial Transplant. 34:49–62. 2019.PubMed/NCBI View Article : Google Scholar


Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M and Kalluri R: Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol. 19:2282–2287. 2008.PubMed/NCBI View Article : Google Scholar


Matsumoto K, Xavier S, Chen J, Kida Y, Lipphardt M, Ikeda R, Gevertz A, Caviris M, Hatzopoulos AK, Kalajzic I, et al: Instructive role of the microenvironment in preventing renal fibrosis. Stem Cells Transl Med. 6:992–1005. 2017.PubMed/NCBI View Article : Google Scholar


Chen CL, Chou KJ, Fang HC, Hsu CY, Huang WC, Huang CW, Huang CK, Chen HY and Lee PT: Progenitor-like cells derived from mouse kidney protect against renal fibrosis in a remnant kidney model via decreased endothelial mesenchymal transition. Stem Cell Res Ther. 6(239)2015.PubMed/NCBI View Article : Google Scholar


Xavier S, Vasko R, Matsumoto K, Zullo JA, Chen R, Maizel J, Chander PN and Goligorsky MS: Curtailing endothelial TGF-β signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD. J Am Soc Nephrol. 26:817–829. 2015.PubMed/NCBI View Article : Google Scholar


Li J, Qu X and Bertram JF: Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am J Pathol. 175:1380–1388. 2009.PubMed/NCBI View Article : Google Scholar


Xie T, Chen C, Peng Z, Brown BC, Reisz JA, Xu P, Zhou Z, Song A, Zhang Y, Bogdanov MV, et al: Erythrocyte metabolic reprogramming by sphingosine 1-phosphate in chronic kidney disease and therapies. Circ Res. 127:360–375. 2020.PubMed/NCBI View Article : Google Scholar


Hou T, Xiao Z, Li Y, You YH, Li H, Liu YP, Xi YY, Li J, Duan SB, Liu H, et al: Norcantharidin inhibits renal interstitial fibrosis by downregulating PP2Ac expression. Am J Transl Res. 7:2199–2211. 2015.PubMed/NCBI


Deng Y, Cai Y, Liu L, Lin X, Lu P, Guo Y, Han M and Xu G: Blocking Tyr265 nitration of protein phosphatase 2A attenuates nitrosative stress-induced endothelial dysfunction in renal microvessels. FASEB J. 33:3718–3730. 2019.PubMed/NCBI View Article : Google Scholar


Wright RS, Reeder GS, Herzog CA, Albright RC, Williams BA, Dvorak DL, Miller WL, Murphy JG, Kopecky SL and Jaffe AS: Acute myocardial infarction and renal dysfunction: A high-risk combination. Ann Intern Med. 137:563–570. 2002.PubMed/NCBI View Article : Google Scholar


Rodrigues FB, Bruetto RG, Torres US, Otaviano AP, Zanetta DM and Burdmann EA: Effect of kidney disease on acute coronary syndrome. Clin J Am Soc Nephrol. 5:1530–1536. 2010.PubMed/NCBI View Article : Google Scholar


Barnes JL and Glass Ii WF: Renal interstitial fibrosis: A critical evaluation of the origin of myofibroblasts. Contrib Nephrol. 169:73–93. 2011.PubMed/NCBI View Article : Google Scholar


Tobisawa T, Yano T, Tanno M, Miki T, Kuno A, Kimura Y, Ishikawa S, Kouzu H, Nishizawa K, Yoshida H and Miura T: Insufficient activation of Akt upon reperfusion because of its novel modification by reduced PP2A-B55α contributes to enlargement of infarct size by chronic kidney disease. Basic Res Cardiol. 112(31)2017.PubMed/NCBI View Article : Google Scholar


Sato Y and Yanagita M: Immune cells and inflammation in AKI to CKD progression. Am J Physiol Renal Physiol. 315:F1501–F1512. 2018.PubMed/NCBI View Article : Google Scholar


Rahman MM, Rumzhum NN, Morris JC, Clark AR, Verrills NM and Ammit AJ: Basal protein phosphatase 2A activity restrains cytokine expression: Role for MAPKs and tristetraprolin. Sci Rep. 5(10063)2015.PubMed/NCBI View Article : Google Scholar


Crispin JC, Apostolidis SA, Rosetti F, Keszei M, Wang N, Terhorst C, Mayadas TN and Tsokos GC: Cutting edge: Protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. J Immunol. 188:3567–3571. 2012.PubMed/NCBI View Article : Google Scholar


Hsieh CY, Hsiao G, Hsu MJ, Wang YH and Sheu JR: PMC, a potent hydrophilic α-tocopherol derivative, inhibits NF-κB activation via PP2A but not IKBα-dependent signals in vascular smooth muscle cells. J Cell Mol Med. 18:1278–1289. 2014.PubMed/NCBI View Article : Google Scholar


Yang J, Fan GH, Wadzinski BE, Sakurai H and Richmond A: Protein phosphatase 2A interacts with and directly dephosphorylates RelA. J Biol Chem. 276:47828–47833. 2001.PubMed/NCBI View Article : Google Scholar


Zhang Y, Cuevas S, Asico LD, Escano C, Yang Y, Pascua AM, Wang X, Jones JE, Grandy D, Eisner G, et al: Deficient dopamine D2 receptor function causes renal inflammation independently of high blood pressure. PLoS One. 7(e38745)2012.PubMed/NCBI View Article : Google Scholar


Asghar M, Chugh G and Lokhandwala MF: Inflammation compromises renal dopamine D1 receptor function in rats. Am J Physiol Renal Physiol. 297:F1543–F1549. 2009.PubMed/NCBI View Article : Google Scholar


Yang S, Yao B, Zhou Y, Yin H, Zhang MZ and Harris RC: Intrarenal dopamine modulates progressive angiotensin II-mediated renal injury. Am J Physiol Renal Physiol. 302:F742–F749. 2012.PubMed/NCBI View Article : Google Scholar


Chugh G, Lokhandwala MF and Asghar M: Oxidative stress alters renal D1 and AT1 receptor functions and increases blood pressure in old rats. Am J Physiol Renal Physiol. 300:F133–F138. 2011.PubMed/NCBI View Article : Google Scholar


Yang Y, Zhang Y, Cuevas S, Villar VA, Escano C, D Asico L, Yu P, Grandy DK, Felder RA, Armando I and Jose PA: Paraoxonase 2 decreases renal reactive oxygen species production, lowers blood pressure, and mediates dopamine D2 receptor-induced inhibition of NADPH oxidase. Free Radic Biol Med. 53:437–446. 2012.PubMed/NCBI View Article : Google Scholar


Armando I, Wang X, Villar VA, Jones JE, Asico LD, Escano C and Jose PA: Reactive oxygen species-dependent hypertension in dopamine D2 receptor-deficient mice. Hypertension. 49:672–678. 2007.PubMed/NCBI View Article : Google Scholar


Zhang Y, Jiang X, Qin C, Cuevas S, Jose PA and Armando I: Dopamine D2 receptors' effects on renal inflammation are mediated by regulation of PP2A function. Am J Physiol Renal Physiol. 310:F128–F134. 2016.PubMed/NCBI View Article : Google Scholar


Marasa BS, Xiao L, Rao JN, Zou T, Liu L, Wang J, Bellavance E, Turner DJ and Wang JY: Induced TRPC1 expression increases protein phosphatase 2A sensitizing intestinal epithelial cells to apoptosis through inhibition of NF-kappaB activation. Am J Physiol Cell Physiol. 294:C1277–C1287. 2008.PubMed/NCBI View Article : Google Scholar


Li S, Wang L, Berman MA, Zhang Y and Dorf ME: RNAi screen in mouse astrocytes identifies phosphatases that regulate NF-kappaB signaling. Mol Cell. 24:497–509. 2006.PubMed/NCBI View Article : Google Scholar


Kim SI, Kwak JH, Wang L and Choi ME: Protein phosphatase 2A is a negative regulator of transforming growth factor-beta1-induced TAK1 activation in mesangial cells. J Biol Chem. 283:10753–10763. 2008.PubMed/NCBI View Article : Google Scholar


Jung KJ, Lee EK, Kim SJ, Song CW, Maruyama N, Ishigami A, Kim ND, Im DS, Yu BP and Chung HY: Anti-inflammatory activity of SMP30 modulates NF-κB through protein tyrosine kinase/phosphatase balance. J Mol Med (Berl). 93:343–356. 2015.PubMed/NCBI View Article : Google Scholar

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Shao L, Ma Y, Fang Q, Huang Z, Wan S, Wang J and Yang L: Role of protein phosphatase 2A in kidney disease (Review). Exp Ther Med 22: 1236, 2021
Shao, L., Ma, Y., Fang, Q., Huang, Z., Wan, S., Wang, J., & Yang, L. (2021). Role of protein phosphatase 2A in kidney disease (Review). Experimental and Therapeutic Medicine, 22, 1236.
Shao, L., Ma, Y., Fang, Q., Huang, Z., Wan, S., Wang, J., Yang, L."Role of protein phosphatase 2A in kidney disease (Review)". Experimental and Therapeutic Medicine 22.5 (2021): 1236.
Shao, L., Ma, Y., Fang, Q., Huang, Z., Wan, S., Wang, J., Yang, L."Role of protein phosphatase 2A in kidney disease (Review)". Experimental and Therapeutic Medicine 22, no. 5 (2021): 1236.