Pentosan polysulfate ameliorates apoptosis and inflammation by suppressing activation of the p38 MAPK pathway in high glucose‑treated HK‑2 cells

Chen,Ping; Yuan,Yang; Zhang,Tianying; Xu,Bo; Gao,Qing; Guan,Tianjun

doi:10.3892/ijmm.2017.3290

Pentosan polysulfate ameliorates apoptosis and inflammation by suppressing activation of the p38 MAPK pathway in high glucose‑treated HK‑2 cells

Authors:
- Ping Chen
- Yang Yuan
- Tianying Zhang
- Bo Xu
- Qing Gao
- Tianjun Guan
View Affiliations

Affiliations: Department of Nephrology, Ningbo First Hospital, Ningbo, Zhejiang 315010, P.R. China, Department of Nephrology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian 361004, P.R. China
Published online on: November 27, 2017 https://doi.org/10.3892/ijmm.2017.3290
Pages: 908-914
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The apoptosis of tubular epithelial cells in diabetic nephropathy (DN) is commonly observed in human renal biopsies. Inflammation plays a key role in DN, and pentosan polysulfate (PPS) has been shown to largely attenuate the inflammation of nephropathy in aging diabetic mice. p38 mitogen‑activated protein kinase (p38 MAPK) plays a crucial role in tissue inflammation and cell apoptosis, and it is activated by hyperglycemia. In the present study, high glucose (HG)‑treated human renal proximal tubular epithelial cells (HK‑2) were used to examine the protective effects of PPS against HG‑stimulated apoptosis and inflammation. The results of the study revealed that PPS markedly suppressed the HG‑induced reduction in cell viability. Incubation of HK‑2 cells with HG activated the p38 MAPK pathway and, subsequently, as confirmed by western blot analysis and flow cytometry, increased cell apoptosis, which was blocked by PPS. In addition, PPS treatment significantly inhibited HG‑stimulated p38 MAPK and nuclear factor‑κB activation, and reduced the production of pro‑inflammatory cytokines, such as tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6. In conclusion, PPS ameliorates p38 MAPK‑mediated renal cell apoptosis and inflammation. The anti‑apoptotic actions and anti‑inflammatory effects of PPS prompt further investigation of this compound as a promising therapeutic agent against DN.

View Figures

View References

1	Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML and Zelmanovitz T: Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care. 28:164–176. 2005. View Article : Google Scholar
2	Tan AL, Forbes JM and Cooper ME: AGE, RAGE, and ROS in diabetic nephropathy. Semin Nephrol. 27:130–143. 2007. View Article : Google Scholar : PubMed/NCBI
3	Magee GM, Bilous RW, Cardwell CR, Hunter SJ, Kee F and Fogarty DG: Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Diabetologia. 52:691–697. 2009. View Article : Google Scholar : PubMed/NCBI
4	Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al: Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature. 404:787–790. 2000. View Article : Google Scholar : PubMed/NCBI
5	Navarro-González JF and Mora-Fernández C: The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol. 19:433–442. 2008. View Article : Google Scholar : PubMed/NCBI
6	Noh H and King GL: The role of protein kinase C activation in diabetic nephropathy. Kidney Int Suppl. 72(Suppl): S49–S53. 2007. View Article : Google Scholar
7	Magri CJ and Fava S: The role of tubular injury in diabetic nephropathy. Eur J Intern Med. 20:551–555. 2009. View Article : Google Scholar : PubMed/NCBI
8	Gilbert RE and Cooper ME: The tubulointerstitium in progressive diabetic kidney disease: More than an aftermath of glomerular injury. Kidney Int. 56:1627–1637. 1999. View Article : Google Scholar : PubMed/NCBI
9	Mora C and Navarro JF: Inflammation and diabetic nephropathy. Curr Diab Rep. 6:463–468. 2006. View Article : Google Scholar : PubMed/NCBI
10	Tuttle KR: Linking metabolism and immunology: Diabetic nephropathy is an inflammatory disease. J Am Soc Nephrol. 16:1537–1538. 2005. View Article : Google Scholar : PubMed/NCBI
11	Kumar D, Robertson S and Burns KD: Evidence of apoptosis in human diabetic kidney. Mol Cell Biochem. 259:67–70. 2004. View Article : Google Scholar : PubMed/NCBI
12	Verzola D, Bertolotto MB, Villaggio B, Ottonello L, Dallegri F, Salvatore F, Berruti V, Gandolfo MT, Garibotto G and Deferrari G: Oxidative stress mediates apoptotic changes induced by hyperglycemia in human tubular kidney cells. J Am Soc Nephrol. 15(Suppl 1): S85–S87. 2004. View Article : Google Scholar
13	Verzola D, Bertolotto MB, Villaggio B, Ottonello L, Dallegri F, Frumento G, Berruti V, Gandolfo MT, Garibotto G and Deferran G: Taurine prevents apoptosis induced by high ambient glucose in human tubule renal cells. J Investig Med. 50:443–451. 2002. View Article : Google Scholar : PubMed/NCBI
14	Stambe C, Nikolic-Paterson DJ, Hill PA, Dowling J and Atkins RC: p38 mitogen-activated protein kinase activation and cell localization in human glomerulonephritis: Correlation with renal injury. J Am Soc Nephrol. 15:326–336. 2004. View Article : Google Scholar : PubMed/NCBI
15	Adhikary L, Chow F, Nikolic-Paterson DJ, Stambe C, Dowling J, Atkins RC and Tesch GH: Abnormal p38 mitogen-activated protein kinase signalling in human and experimental diabetic nephropathy. Diabetologia. 47:1210–1222. 2004. View Article : Google Scholar : PubMed/NCBI
16	Chen H, Brahmbhatt S, Gupta A and Sharma AC: Duration of streptozotocin-induced diabetes differentially affects p38-mitogen-activated protein kinase (MAPK) phosphorylation in renal and vascular dysfunction. Cardiovasc Diabetol. 4:32005. View Article : Google Scholar : PubMed/NCBI
17	Du Y, Tang J, Li G, Berti-Mattera L, Lee CA, Bartkowski D, Gale D, Monahan J, Niesman MR, Alton G, et al: Effects of p38 MAPK inhibition on early stages of diabetic retinopathy and sensory nerve function. Invest Ophthalmol Vis Sci. 51:2158–2164. 2010. View Article : Google Scholar : PubMed/NCBI
18	Nickel JC, Barkin J, Forrest J, Mosbaugh PG, Hernandez-Graulau J, Kaufman D, Lloyd K, Evans RJ, Parsons CL and Atkinson LE; Elmiron Study Group: Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology. 65:654–658. 2005. View Article : Google Scholar : PubMed/NCBI
19	Wu J, Guan TJ, Zheng S, Grosjean F, Liu W, Xiong H, Gordon R, Vlassara H, Striker GE and Zheng F: Inhibition of inflammation by pentosan polysulfate impedes the development and progression of severe diabetic nephropathy in aging C57B6 mice. Lab Invest. 91:1459–1471. 2011. View Article : Google Scholar : PubMed/NCBI
20	Wu H, Shi Y, Deng X, Su Y, Du C, Wei J, Ren Y, Wu M, Hou Y and Duan H: Inhibition of c-Src/p38 MAPK pathway ameliorates renal tubular epithelial cells apoptosis in db/db mice. Mol Cell Endocrinol. 417:27–35. 2015. View Article : Google Scholar : PubMed/NCBI
21	Rane MJ, Song Y, Jin S, Barati MT, Wu R, Kausar H, Tan Y, Wang Y, Zhou G, Klein JB, et al: Interplay between Akt and p38 MAPK pathways in the regulation of renal tubular cell apoptosis associated with diabetic nephropathy. Am J Physiol Renal Physiol. 298:F49–F61. 2010. View Article : Google Scholar :
22	Iwayama H and Ueda N: Role of mitochondrial Bax, caspases, and MAPKs for ceramide-induced apoptosis in renal proximal tubular cells. Mol Cell Biochem. 379:37–42. 2013. View Article : Google Scholar : PubMed/NCBI
23	Blantz RC and Singh P: Glomerular and tubular function in the diabetic kidney. Adv Chronic Kidney Dis. 21:297–303. 2014. View Article : Google Scholar : PubMed/NCBI
24	Baba K, Minatoguchi S, Sano H, Kagawa T, Murata I, Takemura G, Hirano T, Ohashi H, Takemura M, Fujiwara T, et al: Involvement of apoptosis in patients with diabetic nephropathy: A study on plasma soluble Fas levels and pathological findings. Nephrology (Carlton). 9:94–99. 2004. View Article : Google Scholar
25	Habib SL: Diabetes and renal tubular cell apoptosis. World J Diabetes. 4:27–30. 2013. View Article : Google Scholar : PubMed/NCBI
26	Sakai N, Wada T, Furuichi K, Iwata Y, Yoshimoto K, Kitagawa K, Kokubo S, Kobayashi M, Hara A, Yamahana J, et al: Involvement of extracellular signal-regulated kinase and p38 in human diabetic nephropathy. Am J Kidney Dis. 45:54–65. 2005. View Article : Google Scholar : PubMed/NCBI
27	Fujita H, Omori S, Ishikura K, Hida M and Awazu M: ERK and p38 mediate high-glucose-induced hypertrophy and TGF-beta expression in renal tubular cells. Am J Physiol Renal Physiol. 286:F120–F126. 2004. View Article : Google Scholar
28	Bocanegra V, Gil Lorenzo AF, Cacciamani V, Benardón ME, Costantino VV and Vallés PG: RhoA and MAPK signal transduction pathways regulate NHE1-dependent proximal tubule cell apoptosis after mechanical stretch. Am J Physiol Renal Physiol. 307:F881–F889. 2014. View Article : Google Scholar : PubMed/NCBI
29	Galkina E and Ley K: Leukocyte recruitment and vascular injury in diabetic nephropathy. J Am Soc Nephrol. 17:368–377. 2006. View Article : Google Scholar : PubMed/NCBI
30	Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC and Tesch GH: Macrophages in mouse type 2 diabetic nephropathy: Correlation with diabetic state and progressive renal injury. Kidney Int. 65:116–128. 2004. View Article : Google Scholar
31	Sassy-Prigent C, Heudes D, Mandet C, Bélair MF, Michel O, Perdereau B, Bariéty J and Bruneval P: Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. Diabetes. 49:466–475. 2000. View Article : Google Scholar : PubMed/NCBI
32	Furuta T, Saito T, Ootaka T, Soma J, Obara K, Abe K and Yoshinaga K: The role of macrophages in diabetic glomerulosclerosis. Am J Kidney Dis. 21:480–485. 1993. View Article : Google Scholar : PubMed/NCBI
33	Bohle A, Wehrmann M, Bogenschütz O, Batz C, Müller CA and Müller GA: The pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of 488 cases of diabetic glomerulosclerosis. Pathol Res Pract. 187:251–259. 1991. View Article : Google Scholar : PubMed/NCBI
34	Viedt C and Orth SR: Monocyte chemoattractant protein-1 (MCP-1) in the kidney: Does it more than simply attract monocytes. Nephrol Dial Transplant. 17:2043–2047. 2002. View Article : Google Scholar : PubMed/NCBI
35	Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC, Rollin BJ and Tesch GH: Monocyte chemoattractant protein-1 promotes the development of diabetic renal injury in streptozotocin-treated mice. Kidney Int. 69:73–80. 2006. View Article : Google Scholar
36	Chow FY, Nikolic-Paterson DJ, Ma FY, Ozols E, Rollins BJ and Tesch GH: Monocyte chemoattractant protein-1-induced tissue inflammation is critical for the development of renal injury but not type 2 diabetes in obese db/db mice. Diabetologia. 50:471–480. 2007. View Article : Google Scholar
37	Lim AK and Tesch GH: Inflammation in diabetic nephropathy. Mediators Inflamm. 146154:2012. View Article : Google Scholar : PubMed/NCBI
38	Chow FY, Nikolic-Paterson DJ, Ozols E, Atkins RC and Tesch GH: Intercellular adhesion molecule-1 deficiency is protective against nephropathy in type 2 diabetic db/db mice. J Am Soc Nephrol. 16:1711–1722. 2005. View Article : Google Scholar : PubMed/NCBI
39	Okada S, Shikata K, Matsuda M, Ogawa D, Usui H, Kido Y, Nagase R, Wada J, Shikata Y and Makino H: Intercellular adhesion molecule-1-deficient mice are resistant against renal injury after induction of diabetes. Diabetes. 52:2586–2593. 2003. View Article : Google Scholar : PubMed/NCBI
40	Sanchez AP and Sharma K: Transcription factors in the pathogenesis of diabetic nephropathy. Expert Rev Mol Med. 11:e132009. View Article : Google Scholar : PubMed/NCBI
41	Saklatvala J: The p38 MAP kinase pathway as a therapeutic target in inflammatory disease. Curr Opin Pharmacol. 4:372–377. 2004. View Article : Google Scholar : PubMed/NCBI
42	Mezzano S, Aros C, Droguett A, Burgos ME, Ardiles L, Flores C, Schneider H, Ruiz-Ortega M and Egido J: NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy. Nephrol Dial Transplant. 19:2505–2512. 2004. View Article : Google Scholar : PubMed/NCBI
43	Yang B, Hodgkinson A, Oates PJ, Millward BA and Demaine AG: High glucose induction of DNA-binding activity of the transcription factor NFkappaB in patients with diabetic nephropathy. Biochim Biophys Acta. 1782:295–302. 2008. View Article : Google Scholar : PubMed/NCBI
44	Lewko B and Stepinski J: Hyperglycemia and mechanical stress: Targeting the renal podocyte. J Cell Physiol. 221:288–295. 2009. View Article : Google Scholar : PubMed/NCBI