Nephrology · Vol. 1, No. 2 · 2015 · pp. 20–24 · e-ISSN 2380-0445

Current Opinion in the Treatment of Diabetic Nephropathy

Xin-Ming Chen, Chunling Huang, Carol A. Pollock

Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, St. Leonards, New South Wales, Sydney 2065, AustraliaAustralia

DOI: https://doi.org/10.17140/npoj-1-104 · Published 2015-06-26 · Licence: https://creativecommons.org/licenses/by/4.0 · © 2015 The Author(s)

Also available as PDF (figures and tables appear in the PDF).

Abstract

Diabetic nephropathy is a leading cause of end-stage renal failure. Approximately 20-40% patients with diabetes mellitus will develop nephropathy with a significant proportion requiring regular dialysis or kidney transplantation. The International Diabetes Federation estimates that 366 million people had diabetes worldwide in 2011 and 552 million people will have this disease by 2030.1 The increasing incidence of diabetes elevates diabetic nephropathy to one of the most important current public health issues, representing a significant burden on the health system.2 Despite current interventional strategies being intensively implemented, the number of patients with diabetes requiring renal replacement therapy for end-stage renal disease is growing.3 Current treatments of diabetic nephropathy slow its progression,3 so the optimal therapeutic strategy to arrest or reverse the nephropathy is needed urgently. As multiple risk factors and their interactions promote the development of diabetic nephropathy, targeting a single factor may be ineffective in the treatment of this disease; thus, optimal treatments by targeting multiple factors need to be developed to arrest or reverse the diabetic nephropathy

Keywords: Diabetic nephropathy; Autophagy; MicroRNA; Chronic inflammation; Nlrp3; mTOR; AMPK and Sirt1; Diabetic nephropathy; Autophagy; MicroRNA; Chronic inflammation; Nlrp3; Volume 1 : Issue 2 mTOR; AMPK and Sirt1

Acknowledgment

chondria are known to be a major intracellular source of ROS.42 Under pathological conditions such as diabetes, uncoupling of This work was supported by the Juvenile Diabetes Research oxidative phosphorylation and loss of mitochondrial membrane Foundation International.

integrity induce excessive ROS production from the respiratory chain, while excessive ROS leads to further mitochondrial dys-

References

  1. NickersonHDDuttaS. Diabetic complications: current chalcumulation of cytotoxic mediators and cell death. Mitophagy, a lenges and opportunities. J Cardiovasc Transl Res. 2012; 5: 375biological process of autophagic removal of damaged mitochon- 379. doi: 10.1007/s12265-012-9388-1 dria, is important as dysfunctional mitochondria may enhance cellular oxidative stress, generate apoptotic signals, and induce10.1007/s12265-012-9388-1 https://doi.org/10.1007/s12265-012-9388-1
  2. JhaVGarcia-GarciaGIsekiK. Chronic kidney disease: cell death. To date, autophagy is the sole known mechanism for global dimension and perspectives. Lancet. 2013; 382: 260-272. mitochondrial turnover. Fragmented mitochondria are engulfed doi: 10.1016/S0140-6736(13)60687-X by autophogasomes via mitophagy and emerging evidence has suggested mitochondrial fragmentation is characteristic of renal10.1016/s0140-6736(13)60687-x https://doi.org/10.1016/s0140-6736(13)60687-x
  3. LimA. Diabetic nephropathy-complications and treatment. diseases, including diabetic nephropathy.42 In response to re-International journal of nephrology and renovascular disease. duced cellular ATP, AMPK is activated, which phosphorylates 2014; 7: 361-381. doi: 10.2147/IJNRD.S40172 ULK1 and ULK2 (two Atg1 homologues) to activate both general autophagy and mitophagy. In response to stress, induction10.2147/ijnrd.s40172 https://doi.org/10.2147/ijnrd.s40172
  4. TervaertTWMooyaartALAmannK. Pathologic clasof mitophagy results in selective clearance of damaged mitosification of diabetic nephropathy. J Am Soc Nephrol. 2010; 21: chondria in cells. Autophagic removal of damaged mitochondria 556-563. doi: 10.1681/ASN.2010010010 requires two steps: induction of general autophagy and priming of damaged mitochondria for selective autophagic recognition10.1681/asn.2010010010 https://doi.org/10.1681/asn.2010010010
  5. Mora-Fernandez C, Dominguez-Pimentel V, de Fuentes mediated either by the Pink1-Parkin signalling pathway or the MM, et al. Diabetic kidney disease: from physiology to theramitophagic receptors Nix and Bnip3.44 Dysfunction of mitopeutics. J Physiol. 2014; 592: 3997-4012. doi: 10.1113/jphysi- 42,45 chondria in diabetic kidneys has been well reviewed. Studies ol.2014.272328 from animal models indicate that disturbances in mitochondrial homeostasis are central to the pathogenesis of diabetic kidney https://doi.org/10.1113/jphysi-42,45
  6. BadalSSDaneshFR. New insights into molecular mechadisease.46 Collectively, functionally restoring the autophagy and nisms of diabetic kidney disease. Am J Kidney Dis. 2014; 63: mitophagy in kidney may be an effective strategy to arrest the S63-S83. doi: 10.1053/j.ajkd.2013.10.047 progression of diabetic nephropathy. However, to date there is not specific pharmacological activator or inducer of autophagy10.1053/j.ajkd.2013.10.047 https://doi.org/10.1053/j.ajkd.2013.10.047
  7. ForbesJMCooperME. Mechanisms of diabetic complicaand mitophagy available. tions. Physiological reviews. 2013; 93: 137-188. doi: 10.1152/ physrev.00045.2011 In conclusion, the complications of diabetes mellitus, such as nephropathy, parallel its rapidly increasing incidence
  8. ChanGCTangSC. Diabetic nephropathy: landmark cliniwith resultant devastating personal and societal impacts. A succal trials and tribulations. Nephrology, dialysis, transplantation: cessful continuum between innovative discovery science and official publication of the European Dialysis and Transplant rigorous translation of research findings is required to limit the Association-European Renal Association. 2015. doi: 10.1093/ development, and improve the outcomes of patients with existndt/gfu411 ing diabetic nephropathy. However, diabetic kidney disease is complex and multifactorial and the current therapies are largely
  9. FinebergDJandeleit-DahmKACooperME. Diabetic neineffective, therefore there is increasing urgency to identify novphropathy: diagnosis and treatment. Nature reviews. Endocri-
  10. MengXMNikolic-PatersonDJLanHY. Inflammatory pro- 710-719. doi: 10.1152/physiolgenomics.00028.2013 cesses in renal fibrosis. Nature reviews. Nephrology. 2014; 10: 493-503. doi:10.1038/nrneph.2014.114 23. Lim AK, Tesch GH. Inflammation in diabetic nephropathy. Mediators of inflammation. 2012; 2012: 146154. doi:10.1152/physiolgenomics.00028.2013 https://doi.org/10.1152/physiolgenomics.00028.2013
  11. WadaJMakinoH. Inflammation and the pathogenesis of 10.1155/2012/146154 diabetic nephropathy. Clinical science. 2013; 124: 139-152. doi: 10.1042/CS20120198 24. Latz E, Xiao TS, Stutz A. Activation and regulation of the inflammasomes. Nature reviews. Immunology. 2013; 13: 397-10.1155/2012/146154 https://doi.org/10.1155/2012/146154
  12. GomezIGGrafalsMPortillaDDuffieldJS. MicroRNAs 411. doi: 10.1038/nri3452 as potential therapeutic targets in kidney disease. Journal of the Formosan Medical Association=Taiwan yi zhi. 2013; 112: 237- 25. Baroja-Mazo A, Martin-Sanchez F, Gomez AI, et al. The 243. doi: 10.1016/j.jfma.2012.12.011 NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nature immunology10.1038/nri3452 https://doi.org/10.1038/nri3452
  13. LiRChungACYuXLanHY. MicroRNAs in Diabetic 2014; 15: 738-748. doi: 10.1038/ni.2919 Kidney Disease. International journal of endocrinology. 2014; 2014: 593956. doi: 10.1155/2014/593956 26. Ozaki E, Campbell M, Doyle SL. Targeting the NLRP3 inflammasome in chronic inflammatory diseases: current perspec-10.1038/ni.2919 https://doi.org/10.1038/ni.2919
  14. KhellaHWBakhetMLichnerZ. MicroRNAs in kidtives. Journal of inflammation research. 2015; 8: 15-27. doi: ney disease: an emerging understanding. Am J Kidney Dis. 2013; 10.2147/JIR.S51250 61: 798-808. doi: 10.1053/j.ajkd.2012.09.018 27. Vilaysane A, Chun J, Seamone ME, et al. The NLRP3 in-10.2147/jir.s51250 https://doi.org/10.2147/jir.s51250
  15. SchenaFPSerinoGSallustioF. MicroRNAs in kidney disflammasome promotes renal inflammation and contributes to eases: new promising biomarkers for diagnosis and monitoring. CKD. J Am Soc Nephrol. 2010; 21: 1732-1744. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association-European Renal 28. Shahzad K, Bock F, Dong W, et al. Nlrp3-inflammasome Association. 2014; 29: 755-763. doi: 10.1093/ndt/gft223 activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int. 2015; 87: 74-8410.1093/ndt/gft223 https://doi.org/10.1093/ndt/gft223
  16. SrivastavaSPKoyaDKanasakiK. MicroRNAs in kidney fibrosis and diabetic nephropathy: roles on EMT and End- 29. Chang A, Ko K, Clark MR. The emerging role of the in-MT. BioMed research international. 2013; 2013: 125469. doi: flammasome in kidney diseases. Current opinion in nephrol- 10.1155/2013/125469 ogy and hypertension. 2014; 23: 204-210. doi: 10.1097/01. mnh.0000444814.49755.9010.1155/2013/125469 https://doi.org/10.1155/2013/125469
  17. TanakaYKumeSKitadaM. Autophagy as a therapeutic target in diabetic nephropathy. Experimental diabetes re- 30. McClelland AD, Kantharidis P. microRNA in the developsearch. 2012; 2012: 628978. doi: 10.1155/2012/628978 ment of diabetic complications. Clinical science. 2014; 126: 95- 110. doi: 10.1042/CS2013007910.1155/2012/628978 https://doi.org/10.1155/2012/628978
  18. FangLZhouYCaoH. Autophagy attenuates diabetic glomerular damage through protection of hyperglycemia-in- 31. Wu H, Kong L, Zhou S, et al. The role of microRNAs in duced podocyte injury. PloS one. 2013; 8: e60546. doi: 10.1371/ diabetic nephropathy. Journal of diabetes research. 2014; 2014: journal.pone.0060546 920134. doi: 10.1155/2014/92013410.1155/2014/920134 https://doi.org/10.1155/2014/920134
  19. DingYChoiME. Autophagy in diabetic nephropathy. The 32. Putta S, Lanting L, Sun G, et al. Inhibiting microRNA-192 Journal of endocrinology. 2015; 224: R15-R30. doi: 10.1530/ ameliorates renal fibrosis in diabetic nephropathy. J Am Soc JOE-14-0437 Nephrol. 2012; 23: 458-469. doi: 10.1681/ASN.201105048510.1681/asn.2011050485 https://doi.org/10.1681/asn.2011050485
  20. WangZChoiME. Autophagy in kidney health and dis- 33. Wang B, Komers R, Carew R, et al. Suppression of microRease. Antioxid Redox Signal. 2014; 20: 519-537. doi: 10.1089/ NA-29 Expression by TGF-beta1 Promotes Collagen Expresars.2013.5363 sion and Renal Fibrosis. J Am Soc Nephrol. 2012; 23: 252-265. doi: 10.1681/ASN.201101005510.1681/asn.2011010055 https://doi.org/10.1681/asn.2011010055
  21. KumeSYamaharaKYasudaM. Autophagy: Emerging Therapeutic Target for Diabetic Nephropathy. Semin Nephrol. 34. Wang B, Koh P, Winbanks C, et al. miR-200a Prevents Renal 2014; 34: 9-16. doi: 10.1016/j.semnephrol.2013.11.003 Fibrogenesis Through Repression of TGF-{beta}2 Expression. Diabetes. 2011; 60: 280-287. doi: 10.2337/db10-089210.1016/j.semnephrol.2013.11.003 https://doi.org/10.1016/j.semnephrol.2013.11.003