NF‑κB upregulates ubiquitin C‑terminal hydrolase 1 in diseased podocytes in glomerulonephritis

Zhang,Hongxia; Mao,Xing; Sun,Yu; Hu,Ruimin; Luo,Weili; Zhao,Zhonghua; Chen,Qi; Zhang,Zhigang

doi:10.3892/mmr.2015.3780

NF‑κB upregulates ubiquitin C‑terminal hydrolase 1 in diseased podocytes in glomerulonephritis

Authors:
- Hongxia Zhang
- Xing Mao
- Yu Sun
- Ruimin Hu
- Weili Luo
- Zhonghua Zhao
- Qi Chen
- Zhigang Zhang
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Affiliations: Department of Pathology, Weifang Medical College, Weifang, Shandong 261053, P.R. China, Department of Pathology and Key Laboratory of Molecular Medicine (Ministry of Education), College of Basic Medicine, Fudan University, Shanghai 200032, P.R. China
Published online on: May 13, 2015 https://doi.org/10.3892/mmr.2015.3780
Pages: 2893-2901

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Abstract

Podocyte injury is a pivotal factor during the progression of glomerular diseases. It has been demonstrated that the expression of ubiquitin carboxy‑terminal hydrolase L1 (UCH‑L1) is increased in injured podocytes in a number of types of glomerulonephritis. However, its mechanism of regulation remains to be elucidated. A previous study by our group suggested that UCH‑L1 is a downstream protein of nuclear factor (NF)‑κB signaling. In the present study, the involvement of NF‑κB in the regulation of the expression of UCH‑L1 was investigated in diseased podocytes in vivo and in vitro. Increases in the expression of phosphorylated NF‑κB at p65 and UCH‑L1 were detected using immunohistochemical analysis of kidney biopsy tissues from 56 cases of nephritis, including immunoglobulin A nephropathy, membranous glomerulonephritis and lupus nephritis. The two indicators were also analyzed using western blot analysis in cultured murine podocytes stimulated by inflammatory factors. The results of the present study demonstrated that in human renal biopsies of several cases of immune complex‑mediated glomerulonephritis, the increases of NF‑κB and UCH‑L1 were positively correlated with the number of diseased podocytes. By contrast, in non‑immune complex‑mediated glomerulonephritis, no clear activation of NF‑κB and increase of UCH‑L1 expression was observed. In vitro, immune stimulation also led to the upregulation of UCH‑L1 through the NF‑κB signaling pathway in mouse podocytes. In conclusion, the results of the present study suggested that the activation of NF‑κB and upregulation of UCH‑L1 in podocytes may be vital in podocyte injury associated with immune complex‑mediated glomerulonephritis.

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1	Meyer-Schwesinger C, Meyer TN, Sievert H, Hoxha E, Sachs M, Klupp EM, Münster S, Balabanov S, Carrier L, Helmchen U, et al: Ubiquitin c-terminal hydrolase-l1 activity induces polyubiquitin accumulation in podocytes and increases proteinuria in rat membranous nephropathy. Am J Pathol. 178:2044–2057. 2011. View Article : Google Scholar : PubMed/NCBI
2	Liu Y, Wu J, Wu H, Wang T, Gan H, Zhang X, Liu Y, Li RX, Zhao Z, Chen Q, Guo MY and Zhang Z: Uch-l1 expression of podocytes in diseased glomeruli and in vitro. J Pathol. 217:642–653. 2009. View Article : Google Scholar : PubMed/NCBI
3	Greka A and Mundel P: Cell biology and pathology of podocytes. Annu Rev Physiol. 74:299–323. 2012. View Article : Google Scholar
4	Liu X, Ye L, Christianson G, Yang JQ, Roopenian DC and Zhu X: Nf-kappab signaling regulates functional expression of the MHC class I-related neonatal FC receptor for IgG via intronic binding sequences. J Immunol. 179:2999–3011. 2007. View Article : Google Scholar : PubMed/NCBI
5	Guijarro C and Egido J: Transcription factor-kB (NF-kB) and renal disease. Kidney Int. 59:415–424. 2001. View Article : Google Scholar : PubMed/NCBI
6	Baeuerle PA: Pro-inflammatory signaling: last pieces in the NF-kappaB puzzle? Curr Biol. 8:R19–R22. 1998. View Article : Google Scholar : PubMed/NCBI
7	Sakurai H, Shigemori N, Hisada Y, Ishizuka T, Kawashima K and Sugita T: Suppression of NF-kappa B and AP-1 activation by glucocorticoids in experimental glomerulonephritis in rats: molecular mechanisms of anti-nephritic action. Biochim Biophs Acta. 1362:252–262. 1997. View Article : Google Scholar
8	Massy ZA, Guijarro C, O’Donnell MP, Kim Y, Kashtan CE, Egido J, Kasiske BL and Keane WF: The central role of nuclear factor-kappa B in mesangial cell activation. Kidney Int. (Suppl 71): 76–79. 1999. View Article : Google Scholar
9	Rovin BH, Dickerson JA, Tan LC and Hebert CA: Activation of nuclear factor-kB correlates with MCP-1 expression by human mesangial cells. Kidney Int. 48:1263–1271. 1995. View Article : Google Scholar : PubMed/NCBI
10	Ashizawa M, Miyazaki M, Abe K, Furusu A, Isomoto H, Harada T, Ozono Y, Sakai H, Koji T and Kohno S: Detection of nuclear factor-kappaB in IgA nephropathy using southwestern histochemistry. Am J Kidney Dis. 42:76–86. 2003. View Article : Google Scholar : PubMed/NCBI
11	Zheng L, Sinniah R and Hsu SI: In situ glomerular expression of activated NF-kappaB in human lupus nephritis and other non-proliferative proteinuric glomerulopathy. Virchows Arch. 448:172–183. 2006. View Article : Google Scholar
12	Bruggeman LA, Drawz PE, Kahoud N, Lin K, Barisoni L and Nelson PJ: TNFR2 interposes the proliferative and NF-kappaB-mediated inflammatory response by podocytes to TNF-alpha. Lab Invest. 91:413–425. 2011. View Article : Google Scholar : PubMed/NCBI
13	Palanisamy N, Kannappan S and Anuradha CV: Genistein modulates NF-kappaB-associated renal inflammation, fibrosis and podocyte abnormalities in fructose-fed rats. Eur J Pharmacol. 667:355–364. 2011. View Article : Google Scholar : PubMed/NCBI
14	Mudge SJ, Paizis K, Auwardt RB, Thomas RJ and Power DA: Activation of nuclear factor-kappa B by podocytes in the autologous phase of passive heymann nephritis. Kidney Int. 59:923–931. 2001. View Article : Google Scholar : PubMed/NCBI
15	Morigi M, Buelli S, Angioletti S, Zanchi C, Longaretti L, Zoja C, Galbusera M, Gastoldi S, Mundel P, Remuzzi G and Benigni A: In response to protein load podocytes reorganize cytoskeleton and modulate endothelin-1 gene: implication for permselective dysfunction of chronic nephropathies. Am J Pathol. 166:1309–1320. 2005. View Article : Google Scholar : PubMed/NCBI
16	Morigi M, Buelli S, Zanchi C, Longaretti L, Macconi D, Benigni A, Moioli D, Remuzzi G and Zoja C: Shigatoxin-induced endothelin-1 expression in cultured podocytes autocrinally mediates actin remodeling. Am J Pathol. 169:1966–1975. 2006. View Article : Google Scholar
17	Bondeva T, Roger T and Wolf G: Differential regulation of toll-like receptor 4 gene expression in renal cells by angiotensin II: dependency on AP1 and PU.1 transcriptional sites. Am J Nephrol. 27:308–314. 2007. View Article : Google Scholar : PubMed/NCBI
18	Yu LX, Lin QX, Liao H, Feng JH, Dong XH and Ye JM: Tgf-beta1 induces podocyte injury through SMAD3-ERK-NF-kappaB pathway and FYN-dependent TRPC6 phosphorylation. Cell Physiol Biochem. 26:869–878. 2010. View Article : Google Scholar
19	Zhang H, Sun Y, Hu R, Luo W, Mao X, Zhao Z, Chen Q and Zhang Z: The regulation of the UCH-l1 gene by transcription factor NF-kB in podocytes. Cell Signal. 25:1574–1585. 2013. View Article : Google Scholar : PubMed/NCBI
20	Fukasawa H: The role of the ubiquitin-proteasome system in kidney diseases. Clin Exp Nephrol. 16:507–517. 2012. View Article : Google Scholar : PubMed/NCBI
21	Amerik AY and Hochstrasser M: Mechanism and function of deubiquitinating enzymes. Biochim Biophys Acta. 1695:189–207. 2004. View Article : Google Scholar : PubMed/NCBI
22	Wilson PO, Barber PC, Day IN, Thompson RJ and Polak JM: The immunolocalization of protein gene product 9.5 using rabbit polyclonal and mouse monoclonal antibodies. Br J Exp Pathol. 69:91–104. 1988.PubMed/NCBI
23	D’Andrea V, Malinovsky L, Berni A, Biancari F, Biassoni L, Di Matteo FM, Corbellini L, Falvo L, Santoni F, Spyrou M and De Antoni E: The immunolocalization of PGP 9.5 in normal human kidney and renal cell carcinoma. G Chir. 18:521–524. 1997.
24	Shirato I, Asanuma K and Takeda Y: Protein gene product 9.5 is selectively localized in parietal epithelial cells of Bowman’s capsule in the rat kidney. J Am Soc Nephrol. 11:2381–2386. 2000.PubMed/NCBI
25	Meyer-Schwesinger C, Meyer TN, Munster S, Klug P, Saleem M, Helmchen U and Stahl RA: A new role for the neuronal ubiquitin C-terminal hydrolase-l1 (UCH-l1) in podocyte process formation and podocyte injury in human glomerulopathies. J Pathol. 217:452–464. 2009. View Article : Google Scholar
26	Zhang M, Guo MY, Chen Q and M JH: The culture of rat glomerular mesangial cells. J Shanghai Med Univ. 207–209. 1995.
27	Chen GP, Guo MY and Zhang YE: Preparation of anti-thy1 serum and establishment of mesangioproliferative glomerulonephritis model in rat. J Clin Exp Pathol. 241–243. 1996.
28	Chiang ML, Hawkins EP, Berry PL, Barrish J and Hill LL: Diagnostic and prognostic significance of glomerular epithelial cell vacuolization and podocyte effacement in children with minimal lesion nephrotic syndrome and focal segmental glomerulosclerosis: An ultrastructural study. Clin Nephrol. 30:8–14. 1988.PubMed/NCBI
29	Wang D, Dai C, Li Y and Liu Y: Canonical WNT/β-catenin signaling mediates transforming growth factor-β1-driven podocyte injury and proteinuria. Kidney Int. 80:1159–1169. 2011. View Article : Google Scholar : PubMed/NCBI
30	Ghayur A, Liu L, Kolb M, Chawla A, Lambe S, Kapoor A and Margetts PJ: Adenovirus-mediated gene transfer of TGF-β1 to the renal glomeruli leads to proteinuria. Am J Pathol. 180:940–951. 2012. View Article : Google Scholar
31	Shankland SJ: The podocyte’s response to injury: role in proteinuria and glomerulosclerosis. Kidney Int. 69:2131–2147. 2006. View Article : Google Scholar : PubMed/NCBI
32	Borza DB, Zhang JJ, Beck LH Jr, C M and Luo W: Mouse models of membranous nephropathy: the road less travelled by. Am J Clin Exp Immunol. 2:135–145. 2013.PubMed/NCBI
33	Meyer-Schwesinger C, Dehde S, Sachs M, Mathey S, Arefi K, Gatzemeier S, Balabanov S, Becker JU, Thaiss F and Meyer TN: Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis. Am J Physiol Renal Physiol. 303:F1015–F1025. 2012. View Article : Google Scholar : PubMed/NCBI
34	Kato T, Mizuno S and Kamimoto M: The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice. Biomed Res. 31:363–369. 2010. View Article : Google Scholar : PubMed/NCBI
35	Greka A and Mundel P: Cell biology and pathology of podocytes. Annu Rev Physiol. 74:299–323. 2012. View Article : Google Scholar
36	Hirota M, Watanabe K, Hamada S, Sun Y, Strizzi L, Mancino M, Nagaoka T, Gonzales M, Seno M, Bianco C and Salomon D: SMAD2 functions as a co-activator of canonical WNT/beta-catenin signaling pathway independent of SMAD4 through histone acetyltransferase activity of p300. Cell Signal. 20:1632–1641. 2008. View Article : Google Scholar : PubMed/NCBI
37	Rangan G, Wang Y and Harris D: NF-kappaB signalling in chronic kidney disease. Front Biosci (Landmark Ed). 14:3496–3522. 2009. View Article : Google Scholar
38	Li QI and Verma M: NF-κB regulation in the immune system. Nat Rev Immunol. 2:725–734. 2002. View Article : Google Scholar : PubMed/NCBI
39	Schjerven H, Brandtzaeg P and Johansen FE: A novel NF-κB/Rel site in intron 1 cooperates with proximal promoter elements to mediate TNF-α-induced transcription of the human polymeric Ig receptor. J Immunol. 167:6412–6420. 2001. View Article : Google Scholar : PubMed/NCBI
40	Nangaku M, Shankland SJ and Couser WG: Cellular response to injury in membranous nephropathy. J Am Soc Nephrol. 16:1195–1204. 2005. View Article : Google Scholar : PubMed/NCBI
41	Rus HG, Niculescu FI and Shin ML: Role of the c5b-9 complement complex in cell cycle and apoptosis. Immunol Rev. 180:49–55. 2001. View Article : Google Scholar : PubMed/NCBI
42	Kazatchkine MD, Fearon DT, Appay MD, Mandet C and Bariety J: Immunohistochemical study of the human glomerular c3b receptor in normal kidney and in seventy-five cases of renal diseases: loss of c3b receptor antigen in focal hyalinosis and in proliferative nephritis of systemic lupus erythematosus. J Clin Invest. 69:900–912. 1982. View Article : Google Scholar : PubMed/NCBI