The role of sirolimus in proteinuria in diabetic nephropathy rats

Document Type : Original Article

Authors

Department of Transplantation, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China

Abstract

Objective(s): The aim of this study was to observe the impact of sirolimus on proteinuria in streptozotocin (STZ) induced diabetic rats.
Materials and Methods: Rats were given a single injection of STZ to induce diabetic rat model. Rats’ 24 hr urine was collected to test, urinary and the kidney tissues were harvested at the 8th and 20th weeks, respectively. Podocyte morphological changes were examined by electron microscopy and the ZO-1, podocin expressions in kidneys were detected by immunohistochemistry; the protein levels of Raptor and pS6 were measured by Western blot assay.
Results: In the early stage of diabetic nephropathy (DN), sirolimus reduced the proteinuria significantly (P<0.05); but in the advanced stage of DN, sirolimus worsened proteinuria (P<0.05). Electron microscopy test suggested that sirolimus could reduce the injury of podocyte at the early DN, but increased the injury at the late DN podocyte. Immunohistochemistry results indicated that sirolimus increased the expressions of podocin and ZO-1 at the early DN (P<0.05), but reduced the expressions of ZO-1 and podocin (P<0.05) at the advanced DN. In the different periods of DN, the expression levels of Raptor and pS6 in sirolimus-treated groups were significantly lower than in the DN control groups (P<0.05).
Conclusion: Sirolimus can reduce proteinuria and alleviate the early DN podocyte injury in diabetic rat model by inhibiting the activity of mTORC1; but in the advanced stage of DN, sirolimus can increase podocyte injury and urine protein level.

Keywords

References

1. Lebranchu Y, Thierry A, Toupance O, Westeel PF, Etienne I, Thervet E, et al. Efficacy on renal function of early conversion from cyclosporine to sirolimus 3 months after renal transplantation: concept study. Am J Transplant 2009; 9:1115-1123.
2. Franco-Esteve A, Tordera D, de la Sen ML, Jiménez L, Mas P, Muñoz C, et al. mTOR inhibitor monotherapy. A good treatment choice in renal transplantation? Nefrologia 2012; 32:631-638.
3. van den Akker JM, Wetzels JF, Hoitsma AJ. Proteinuria following conversion from azathioprine to sirolimus in renal transplant recipients. Kidney Int 2006; 70:1355-1357.
4. Aliabadi AZ, Pohanka E, Seebacher G, Dunkler D, Kammerstätter D, Wolner E, et al. Development of proteinuria after switch to sirolimus-based immunosuppression in long-term cardiac transplant patients. Am J Transplant 2008; 8:854-861.
5. Letavernier E, Bruneval P, Mandet C, Duong Van Huyen JP, Péraldi MN, Helal I, et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol 2007; 2:326-333.
6. Izzedine H, Brocheriou I, Frances C. Post-transplantation proteinuria and sirolimus. N Engl J Med 2005; 353:2088-2089.
7. Kaplan B, Qazi Y, Wellen JR. Strategies for the management of adverse events associated with mTOR inhibitors. Transplant Rev 2014; 28:126-133.
8. Kim BS, Cho Y, Lee H, Joo DJ, Huh KH, Kim MS, et al. Comparative proteomic analysis of rapamycin versus cyclosporine combination treatment in mouse podocytes. Transplant Proc 2016; 48:1297-1301.
9. Müller-Krebs S, Weber L, Tsobaneli J, Kihm LP, Reiser J, Zeier M, et al. Cellular effects of everolimus and sirolimus on podocytes. PLoS One 2013; 8:e80340.
10. Cai Y, Chen Y, Zheng S, Chen B, Yang Y, Xia P. Sirolimus damages podocytes in rats with protein overload nephropathy. J Nephrol 2011; 24:307-312.
11. Menini S, Iacobini C, Oddi G, Ricci C, Simonelli P, Fallucca S, et al. Increased glomerular cell (podocyte) apoptosis in rats with streptozotocin-induced diabetes mellitus: role in the development of diabetic glomerular disease. Diabetologia 2007; 50:2591-2599.
12. Susztak K, Raff AC, Schiffer M, Böttinger EP. Glucose-induced reactive oxygen species cause apoptosis of podocytes and podocyte depletion at the onset of diabetic nephropathy. Diabetes 2006; 55:225-233.
13. Tesch GH, Allen TJ. Rodent models of streptozotocin-induced diabetic nephropathy. Nephrology 2007; 12:261-266.
14. White KE, Bilous RW, Marshall SM, El Nahas M, Remuzzi G, Piras G, et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes 2002; 51:3083-3089.
15. Attia DM, Feron O, Goldschmeding R, Radermakers LH, Vaziri ND, Boer P, et al. Hypercholesterolemia in rats induces podocyte stress and decreases renal cortical nitric oxide synthesis via an angiotensin II type 1 receptor-sensitive mechanism. J Am Soc Nephrol 2004; 15:949-957.
16. Liu XD, Zhang LY, Zhu TC, Zhang RF, Wang SL, Bao Y. Overexpression of miR-34c inhibits high glucose-induced apoptosis in podocytes by targeting Notch signaling pathways. Int J Clin Exp Pathol 2015; 8:4525-4534.
17. Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attié T, et al. Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 2002; 160:131-139.
18. Michaud JL, Lemieux LI, Dubé M, Vanderhyden BC, Robertson SJ, Kennedy CR. Focal and segmental glomerulosclerosis in mice with podocyte-specific expression of mutant alpha-actinin-4. J Am Soc Nephrol J 2003; 14:1200-1211.
19. Rincon-Choles H, Vasylyeva TL, Pergola PE, Bhandari B, Bhandari K, Zhang JH, et al. ZO-1 expression and phosphorylation in diabetic nephropathy. Diabetes 2006; 55:894-900.
20. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006; 124:471-484.
21. Kim DH, Sabatini DM. Raptor and mTOR: subunits of a nutrient-sensitive complex. Curr Top Microbiol Immunol 2004; 279:259-270.
22. Thomas G. The S6 kinase signaling pathway in the control of development and growth. Biol Res 2002; 35:305-313.
23. Li LC, Hsu CN, Lin CC, Cheng YF, Hu TH, Chen DW, et al. Proteinuria and baseline renal function predict mortality and renal outcomes after sirolimus therapy in liver transplantation recipients. BMC Gastroenterol 2017; 17:58.
24. Mjörnstedt L, Sørensen SS, von Zur Mühlen B, Jespersen B, Hansen JM, Bistrup C, et al. Improved renal function after early conversion from a calcineurin inhibitor to everolimus: a randomized trial in kidney transplantation. Am J Transplant 2012; 12:2744-2753.
25. Mandelbrot DA, Alberú J, Barama A, Marder BA, Silva HT Jr, Flechner SM, et al. Effect of ramipril on urinary protein excretion in maintenance renal transplant patients converted to sirolimus. Am J Transplant 2015; 15:3174-3184.
26. Taveira-DaSilva AM, Jones AM, Julien-Williams PA, Stylianou M, Moss J. Retrospective review of combined sirolimus and simvastatin therapy in lymphangioleiomyomatosis. Chest 2015; 147:180-187.
27. Franco A, Más-Serrano P, Perez Contreras J, Jiménez L, Rodriguez D, Olivares J. Mammalian target of rapamycin inhibitor monotherapy: efficacy in renal transplantation. Transplant Proc 2015; 47:2364-2367.
28. Jun H, Kim MG, Jung CW. Clinical advantages including medication adherence with conversion to once-daily advagraf and sirolimuscombination in stable kidney recipients. Int J Clin Pharmacol Ther 2016; 54(2):81-6.
29. Amer H, Cosio FG. Significance and management of proteinuria in kidney transplant recipients. J Am Soc Nephrol 2009; 20:2490-2492.
30. Letavernier E, Bruneval P, Mandet C, Duong Van Huyen JP, Péraldi MN, Helal I, et al. High sirolimus levels may induce focal segmental glomerulosclerosis de novo. Clin J Am Soc Nephrol 2007; 2:326-333.
31. Godel M, Hartleben B, Herbach N, Liu S, Zschiedrich S, Lu S, et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J Clin Invest 2011; 121:2197-2209.
32. Jefferson JA, Shankland SJ, Pichler RH. Proteinuria in diabetic kidney disease: a mechanistic viewpoint. Kidney Int 2008; 74:22-36.
33. Xiao T, Guan X, Nie L, Wang S, Sun L, He T, et al. Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice. Mol Cell Biochem 2014; 394:145-154.
34. Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr Opin Cell Biol 2009; 21:209-218.
35. Mori H, Inoki K, Masutani K, Wakabayashi Y, Komai K, Nakagawa R, et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem Biophys Res Commun 2009; 384:471-475.
36. Hamatani H, Hiromura K, Sakairi T, Takahashi S, Watanabe M, Maeshima A, et al. Expression of a novel stress-inducible protein, sestrin 2, in rat glomerular parietal epithelial cells. Am J Physiol Renal Physiol 2014; 307:F708-F717.
Iranian Journal of Basic Medical Sciences
Volume 20, Issue 12
December 2017
Pages 1339-1344

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