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Molecular Mechanisms of Apoptosis of Glomerular Podocytes in Diabetic Nephropathy

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Biochemistry (Moscow), Supplement Series A: Membrane and Cell Biology Aims and scope

Abstract

Dysfunctions of glomerular podocytes and triggering of apoptotic processes in them are the main molecular causes of diabetic nephropathy and other kidney diseases. Pathogenetic factors causing these dysfunctions of podocytes are hyperglycemia, increased levels of advanced glycation end-products, oxidative stress, increased activity of inflammatory factors, and endoplasmic reticulum stress. These factors and their combinations result in the triggering of a number of intracellular signaling pathways that cause activation of apoptosis and reduce the survival of podocytes. Among these pathways are: (1) the Wnt/β-catenin pathway, which is activated by the Wnt-proteins when they bind to the complex of Frizzled receptors and LRP co-receptors; (2) the mTOR-dependent signaling pathway, including the mTORC1 and mTORC2 complexes, which are involved in the regulation of autophagy and endoplasmic reticulum stress and are regulated by various stimuli and effectors, in particular, the AMP-activated protein kinase; (3) the Rho/ROCK signaling pathway, including GTPases of the Rho family and Rho-associated protein kinase ROCK1; (4) calcium-dependent signaling pathways triggered by an increase in the concentration of intracellular Ca2+, primarily through the activation of calcium channels of the TRPC family. The review provides a detailed analysis of the current state of knowledge about the molecular mechanisms responsible for the regulation of apoptotic processes in glomerular podocytes and also considers hormonal and other factors that regulate them both under normal conditions and under the conditions of lesions induced by hyperglycemia and diabetic nephropathy.

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REFERENCES

  1. Dedov I.I., Shestakova M.V. 2000. Diabeticheskaya nefropatiya (Diabetic nephropathy), Moscow: Universum Publishing.

  2. Lal M.A., Patrakka J. 2018. Understanding podocyte biology to develop novel kidney therapeutics. Front. Endocrinol. (Lausanne). 9, 409. https://doi.org/10.3389/fendo.2018.00409

    Article  Google Scholar 

  3. Torban E., Braun F., Wanner N., Takano T., Goodyer P.R., Lennon R., Ronco P., Cybulsky A.V., Huber T.B. 2019. From podocyte biology to novel cures for glomerular disease. Kidney Int. 96 (4), 850–861. https://doi.org/10.1016/j.kint.2019.05.015

    Article  PubMed  Google Scholar 

  4. Dai H., Liu Q., Liu B. 2017. Research progress on mechanism of podocyte depletion in diabetic nephropathy. J. Diabetes Res. 2017, 2615286. https://doi.org/10.1155/2017/2615286

  5. Tung C.W., Hsu Y.C., Shih Y.H., Chang P.J., Lin C.L. 2018. Glomerular mesangial cell and podocyte injuries in diabetic nephropathy. Nephrology (Carlton). 23 (Suppl. 4), 32–37. https://doi.org/10.1111/nep.13451

    Article  CAS  Google Scholar 

  6. Lin T.A., Wu V.C., Wang C.Y. 2019. Autophagy in chronic kidney diseases. Cells. 8 (1), pii E61. https://doi.org/10.3390/cells8010061

    Article  CAS  PubMed  Google Scholar 

  7. Willert K., Nusse R. 2012. Wnt proteins. Cold Spring Harb. Perspect. Biol. 4 (9), a007864. https://doi.org/10.1101/cshperspect.a007864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang Y., Chang H., Rattner A., Nathans J. 2016. Frizzled receptors in development and disease. Curr. Top. Dev. Biol. 117, 113–139. https://doi.org/10.1016/bs.ctdb.2015.11.028

    Article  PubMed  PubMed Central  Google Scholar 

  9. Jin T., George Fantus I., Sun J. 2008. Wnt and beyond Wnt: Multiple mechanisms control the transcriptional property of beta-catenin. Cell. Signal. 20 (10), 1697–1704. https://doi.org/10.1016/j.cellsig.2008.04.014

    Article  CAS  PubMed  Google Scholar 

  10. Chiang Y.T., Ip W., Jin T. 2012. The role of the Wnt signaling pathway in incretin hormone production and function. Front. Physiol. 3, 273. https://doi.org/10.3389/fphys.2012.00273

    Article  PubMed  PubMed Central  Google Scholar 

  11. Taurin S., Sandbo N., Qin Y., Browning D., Dulin N.O. 2006. Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J. Biol. Chem. 281 (15), 9971–9976. https://doi.org/10.1074/jbc.M508778200

    Article  CAS  PubMed  Google Scholar 

  12. Zhu G., Wang Y., Huang B., Liang J., Ding Y., Xu A., Wu W. 2012. A Rac1/PAK1 cascade controls beta-catenin activation in colon cancer cells. Oncogene. 31 (8), 1001–1012 https://doi.org/10.1038/onc.2011.294

    Article  CAS  PubMed  Google Scholar 

  13. Wan J., Hou X., Zhou Z., Geng J., Tian J., Bai X., Nie J. 2017. WT1 ameliorates podocyte injury via repression of EZH2/β-catenin pathway in diabetic nephropathy. Free Radic. Biol. Med. 108, 280–299. https://doi.org/10.1016/j.freeradbiomed.2017.03.012

    Article  CAS  PubMed  Google Scholar 

  14. Guo Q., Zhong W., Duan A., Sun G., Cui W., Zhuang X., Liu L. 2019. Protective or deleterious role of Wnt/beta-catenin signaling in diabetic nephropathy: An unresolved issue. Pharmacol. Res. 144, 151–157. https://doi.org/10.1016/j.phrs.2019.03.022

    Article  CAS  PubMed  Google Scholar 

  15. Xiao L., Wang M., Yang S., Liu F., Sun L. 2013. A glimpse of the pathogenetic mechanisms of Wnt/β-catenin signaling in diabetic nephropathy. BioMed Res. Int. 2013, 7. https://doi.org/10.1155/2013/987064.987064

  16. Bose M., Almas S., Prabhakar S. 2017. Wnt signaling and podocyte dysfunction in diabetic nephropathy. J. Investig. Med. 65 (8), 1093–1101. https://doi.org/10.1136/jim-2017-000456

    Article  PubMed  Google Scholar 

  17. Zhou L., Chen X., Lu M., Wu Q., Yuan Q., Hu C., Miao J., Zhang Y., Li H., Hou F.F., Nie J., Liu Y. 2019. Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria. Kidney Int. 95 (4), 830–845. https://doi.org/10.1016/j.kint.2018.10.032

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dai C., Stolz D.B., Kiss L.P., Monga S.P., Holzman L.B., Liu Y. 2009. Wnt/β-catenin signaling promotes podocyte dysfunction and albuminuria. J. Am. Soc. Nephrol. 20 (9), 1997–2008. https://doi.org/10.1681/ASN.2009010019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou T., He X., Cheng R., Zhang B., Zhang R.R., Chen Y., Takahashi Y., Murray A.R., Lee K., Gao G., Ma J.X. 2012. Implication of dysregulation of the canonical wingless-type MMTV integration site (WNT) pathway in diabetic nephropathy. Diabetologia. 55 (1), 255–266. https://doi.org/10.1007/s00125-011-2314-2

    Article  CAS  PubMed  Google Scholar 

  20. Duan S., Wu Y., Zhao C., Chen M., Yuan Y., Xing C., Zhang B. 2016. The wnt/β-catenin signaling pathway participates in rhein ameliorating kidney injury in DN mice. Mol. Cell. Biochem. 411 (1–2), 73–82. https://doi.org/10.1007/s11010-015-2569-x

    Article  CAS  PubMed  Google Scholar 

  21. Guo J., Lu C., Zhang F., Yu H., Zhou M., He M., Wang C., Zhao Z., Liu Z. 2017. VDR activation reduces proteinuria and high-glucose-induced injury of kidneys and podocytes by regulating Wnt signaling pathway. Cell. Physiol. Biochem. 43 (1), 39–51. https://doi.org/10.1159/000480315

    Article  CAS  PubMed  Google Scholar 

  22. Zhou Z., Wan J., Hou X., Geng J., Li X., Bai X. 2017. MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy. Cell Death Dis. 8 (3), e2658. https://doi.org/10.1038/cddis.2017.74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang X., Gao Y., Tian N., Zou D., Shi Y., Zhang N. 2018. Astragaloside IV improves renal function and fibrosis via inhibition of miR-21-induced podocyte dedifferentiation and mesangial cell activation in diabetic mice. Drug Des. Devel. Ther. 6 (12), 2431–2442. https://doi.org/10.2147/DDDT.S170840

    Article  Google Scholar 

  24. Wang Y., Li H., Song S.P. 2018. β-arrestin 1/2 aggravates podocyte apoptosis of diabetic nephropathy via wnt/β-Catenin pathway. Med. Sci. Monit. 24, 1724–1732. https://doi.org/10.12659/msm.905642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Buelli S., Rosant L., Gagliardini E., Corna D., Longaretti L., Pezzotta A., Perico L., Conti S., Rizzo P., Novelli R., Morigi M., Zoja C., Remuzzi G., Bagnato A., Benigni A. 2014. β-arrestin-1 drives endothelin-1-mediated podocyte activation and sustains renal injury. J. Am. Soc. Nephrol. 25 (3), 523–533. https://doi.org/10.1681/ASN.2013040362

    Article  CAS  PubMed  Google Scholar 

  26. Liu J., Li Q.X., Wang X.J., Zhang C., Duan Y.Q., Wang Z.Y., Zhang Y., Yu X., Li N.J., Sun J.P., Yi F. 2016. β-Arrestins promote podocyte injury by inhibition of autophagy in diabetic nephropathy. Cell Death Dis. 7, e2183. https://doi.org/10.1038/cddis.2016.89

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Bowin C.F., Inoue A., Schulte G. 2019. WNT-3A-induced β-catenin signaling does not require signaling through heterotrimeric G proteins. J. Biol. Chem. 294 (31), 11677–11684. https://doi.org/10.1074/jbc.AC119.009412

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Bryja V., Gradl D., Schambony A., Arenas E., Schulte G. 2007. Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo.Proc. Natl. Acad. Sci. USA. 104 (16), 6690–6695. https://doi.org/10.1073/pnas.0611356104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu H., Li Q., Liu J., Zhu J., Li L., Wang Z., Zhang Y., Sun Y., Sun J., Wang R., Yi F. 2018. β-Arrestin-1 deficiency ameliorates renal interstitial fibrosis by blocking Wnt1/β-catenin signaling in mice. J. Mol. Med. (Berl.). 96 (1), 97–109. https://doi.org/10.1007/s00109-017-1606-5

    Article  CAS  Google Scholar 

  30. Cheng R., Ding L., He X., Takahashi Y., Ma J.X. 2016. Interaction of PPARα with the canonic wnt pathway in the regulation of renal fibrosis. Diabetes. 65 (12), 3730–3743. https://doi.org/10.2337/db16-0426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lecarpentier Y., Claes V., Vallée A., Hébert J.L. 2017. Interactions between PPAR gamma and the canonical Wnt/beta-catenin pathway in type 2 diabetes and colon cancer. PPAR Res. 2017, 589090https://doi.org/10.1155/2017/5879090

  32. Lecarpentier Y., Vallée A. 2016. Opposite interplay between PPAR gamma and canonical Wnt/Beta-Catenin pathway in amyotrophic lateral sclerosis. Front. Neurol. 28 (7), 100. https://doi.org/10.3389/fneur.2016.00100

    Article  Google Scholar 

  33. Gao L., Hu Y., Li J. 2017. Pigment epithelium‑derived factor protects human glomerular mesangial cells from diabetes via NOXO1‑iNOS suppression. Mol. Med. Rep. 16 (5), 7855–7863. https://doi.org/10.3892/mmr.2017.7563

    Article  CAS  PubMed  Google Scholar 

  34. He X., Cheng R., Park K., Benyajati S., Moiseyev G., Sun C., Olson L.E., Yang Y., Eby B.K., Lau K., Ma J.X. 2017. Pigment epithelium-derived factor, a noninhibitory serine protease inhibitor, is renoprotective by inhibiting the Wnt pathway. Kidney Int. 91 (3), 642–657. https://doi.org/10.1016/j.kint.2016.09.036

    Article  CAS  PubMed  Google Scholar 

  35. Zhao C., Gao J., Li S., Liu Q., Hou X., Liu S., Xing X., Sun M., Wang S., Luo Y. 2018. Cyclin G2 suppresses glomerulosclerosis by regulating canonical wnt signalling. Biomed. Res. Int. 2018, 69382. https://doi.org/10.1155/2018/6938482

  36. Ma S., Yao S., Tian H., Jiao P., Yang N., Zhu P., Qin S. 2017. Pigment epithelium-derived factor alleviates endothelial injury by inhibiting Wnt/β-catenin pathway. Lipids Health Dis. 16 (1), 31. https://doi.org/10.1186/s12944-017-0407-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chen H., Zheng Z., Li R., Lu J., Bao Y., Ying X., Zeng R., Jia W. 2010. Urinary pigment epithelium-derived factor as a marker of diabetic nephropathy. Am. J. Nephrol. 32 (1), 47–56. https://doi.org/10.1159/000314326

    Article  CAS  PubMed  Google Scholar 

  38. Bernaudo S., Salem M., Qi X., Zhou W., Zhang C., Yang W., Rosman D., Deng Z., Ye G., Yang B.B., Vanderhyden B., Wu Z., Peng C. 2016. Cyclin G2 inhibits epithelial-to-mesenchymal transition by disrupting Wnt/β-catenin signaling. Oncogene. 35 (36), 4816–4827. https://doi.org/10.1038/onc.2016.15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wullschleger S., Loewith R., Hall M.N. 2006. TOR signaling in growth and metabolism. Cell. 124, 471–484. https://doi.org/10.1016/j.cell.2006.01.016

    Article  CAS  PubMed  Google Scholar 

  40. Torres V.E., Boletta A., Chapman A., Gattone V., Pei Y., Qian Q., Wallace D.P., Weimbs T., Wüthrich R.P. 2010. Prospects for mTOR inhibitor use in patients with polycystic kidney disease and hamartomatous diseases. Clin. J. Am. Soc. Nephrol. 5, 1312–1329. https://doi.org/10.2215/CJN.01360210

    Article  CAS  PubMed  Google Scholar 

  41. Sarbassov D.D., Ali S.M., Kim D.H., Guertin D.A., Latek R.R., Erdjument-Bromage H., Tempst P., Sabatini D.M. 2004. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14, 1296–1302. https://doi.org/10.1016/j.cub.2004.06.054

    Article  CAS  PubMed  Google Scholar 

  42. Li Q., Zeng Y., Jiang Q., Wu C., Zhou J. 2019. Role of mTOR signaling in the regulation of high glucose-induced podocyte injury. Exp. Ther. Med. 17 (4), 2495–2502. https://doi.org/10.3892/etm.2019.7236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sakaguchi M., Isono M., Isshiki K., Sugimoto T., Koya D., Kashiwagi A. 2006. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem. Biophys. Res. Commun. 340 (1), 296–301. https://doi.org/10.1016/j.bbrc.2005.12.012

    Article  CAS  PubMed  Google Scholar 

  44. Lei J., Zhao L., Zhang Y., Wu Y., Liu Y. 2018. High glucose-induced podocyte injury involves activation of mammalian target of rapamycin (mTOR)-induced endoplasmic reticulum (ER) stress. Cell. Physiol. Biochem. 45, 2431–2443. https://doi.org/10.1159/000488231

    Article  CAS  PubMed  Google Scholar 

  45. Yuan Y., Xu X., Zhao C., Zhao M., Wang H., Zhang B., Wang N., Mao H., Zhang A., Xing C. 2015. The roles of oxidative stress, endoplasmic reticulum stress, and autophagy in aldosterone mineralocorticoid receptor-induced podocyte injury. Lab. Invest. 95 (12), 1374–1386. https://doi.org/10.1038/labinvest.2015.118

    Article  CAS  PubMed  Google Scholar 

  46. Rong G., Tang X., Guo T., Duan N., Wang Y., Yang L., Zhang J., Liang X. 2015. Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress. J. Physiol. Biochem. 71 (3), 455–470. https://doi.org/10.1007/s13105-015-0424-x

    Article  CAS  PubMed  Google Scholar 

  47. Cao Y., Hao Y., Li H., Liu Q., Gao F., Liu W., Duan H. 2014. Role of endoplasmic reticulum stress in apoptosis of differentiated mouse podocytes induced by high glucose. Int. J. Mol. Med. 33 (4), 809–816. https://doi.org/10.3892/ijmm.2014.1642

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhou H., Liu R. 2014. ER stress and hepatic lipid metabolism. Front. Genet. 5, 112. https://doi.org/10.3389/fgene.2014.00112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhuang A., Forbes J. M. 2014. Stress in the kidney is the road to pERdition: Is endoplasmic reticulum stress a pathogenic mediator of diabetic nephropathy? J. Endocrinol. 222 (3), R97–R111. https://doi.org/10.1530/JOE-13-0517

    Article  CAS  PubMed  Google Scholar 

  50. Appenzeller-Herzog C., Hall M.N. 2012. Bidirectional crosstalk between endoplasmic reticulum stress and mTOR signaling. Trends Cell. Biol. 22 (5), 274–282. https://doi.org/10.1016/j.tcb.2012.02.006

    Article  CAS  PubMed  Google Scholar 

  51. Hosokawa N., Hara T., Kaizuka T., Kishi C., Takamura A., Miura Y., Iemura S., Natsume T., Takehana K., Yamada N., Guan J.L., Oshiro N., Mizushima N. 2009. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol. Biol. Cell. 20 (7), 1981–1991. https://doi.org/10.1091/mbc.E08-12-1248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Hartleben B., Gödel M., Meyer-Schwesinger C., Liu S., Ulrich T., Köbler S., Wiech T., Grahammer F., Arnold S.J., Lindenmeyer M.T., Cohen C.D., Pavenstädt H., Kerjaschki D., Mizushima N., Shaw A.S., Walz G., Huber T.B. 2010. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Invest. 120 (4), 1084–1096. https://doi.org/10.1172/JCI39492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Inoki K., Mori H., Wang J., Suzuki T., Hong S., Yoshida S., Blattner S.M., Ikenoue T., Rüegg M.A., Hall M.N., Kwiatkowski D.J., Rastaldi M.P., Huber T.B., Kretzler M., Holzman L.B., Wiggins R.C., Guan K.L. 2011. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Invest. 121 (6), 2181–2196. https://doi.org/10.1172/JCI44771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Kim J., Kundu M., Viollet B., Guan K.L. 2011. AMPK and mTOR regulate autophagy through direct phosphorylation of UIk1. Nat. Cell. Bio1. 13 (2), 132–141. https://doi.org/10.1038/ncb2152

  55. Wu L., Feng Z., Cui S., Hou K., Tang L., Zhou J., Cai G., Xie Y., Hong Q., Fu B., Chen X. 2013. Rapamycin upregulates autophagy by inhibiting the mTOR-ULK1 pathway, resulting in reduced podocyte injury. PLoS One. 8 (5), e63799. https://doi.org/10.1371/journal.pone.0066745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Xiao T., Guan X., Nie L., Wang S., Sun L., He T., Huang Y., Zhang J., Yang K., Wang J., Zhao J. 2014. Rapamycin promotes podocyte autophagy and ameliorates renal injury in diabetic mice. Mol. Cell. Biochem. 394 (1–2), 145–154. https://doi.org/10.1007/s11010-014-2090-7

    Article  CAS  PubMed  Google Scholar 

  57. Ding Y., Choi M.E. 2015. Autophagy in diabetic nephropathy. J. Endocrinol. 224 (1), R15–R30. https://doi.org/10.1530/JOE-14-0437

    Article  CAS  PubMed  Google Scholar 

  58. Wang J., Xu Z., Chen B., Zheng S., Xia P., Cai Y. 2017. The role of sirolimus in proteinuria in diabetic nephropathy rats. Iran J. Basic Med. Sci. 20 (12), 1339–1344. https://doi.org/10.22038/IJBMS.2017.9618

    Article  PubMed  PubMed Central  Google Scholar 

  59. Liu L., Yang L., Chang B., Zhang J., Guo Y., Yang X. 2018. The protective effects of rapamycin on cell autophagy in the renal tissues of rats with diabetic nephropathy via mTOR-S6K1-LC3II signaling pathway. Ren. Fail. 40 (1), 492–497. https://doi.org/10.1080/0886022X.2018.1489287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yang D., Livingston M.J., Liu Z., Dong G., Zhang M., Chen J.K., Dong Z. 2018. Autophagy in diabetic kidney disease: Regulation, pathological role and therapeutic potential. Cell Mol. Life Sci. 75 (4), 669–688. https://doi.org/10.1007/s00018-017-2639-1

    Article  CAS  PubMed  Google Scholar 

  61. Zhang H.T., Wang W.W., Ren L.H., Zhao X.X., Wang Z.H., Zhuang D.L., Bai Y.N. 2016. The mTORC2/Akt/NFκB pathway-mediated activation of TRPC6 participates in adriamycin-induced podocyte apoptosis. Cell. Physiol. Biochem. 40, 1079–1093. https://doi.org/10.1159/000453163

    Article  CAS  PubMed  Google Scholar 

  62. Ng T., Parsons M., Hughes W.E., Monypenny J., Zicha D., Gautreau A., Arpin M., Gschmeissner S., Verveer P.J., Bastiaens P.I., Parker P.J. 2001. Ezrin is a downstream effector of trafficking PKC-integrin complexes involved in the control of cell motility. EMBO J.20, 2723–2741. https://doi.org/10.1093/emboj/20.11.2723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Bretscher A., Edwards K., Fehon R.G. 2002. ERM proteins and merlin: Integrators at the cell cortex. Nat. Rev. Mol. Cell. Biol. 3, 586–599. https://doi.org/10.1038/nrm882

    Article  CAS  PubMed  Google Scholar 

  64. Wasik A.A., Koskelainen S., Hyvönen M.E., Musante L., Lehtonen E., Koskenniemi K., Tienari J., Vaheri A., Kerjaschki D., Szalay C., Révész C., Varmanen P., Nyman T.A., Hamar P., Holthöfer H., Lehtonen S. 2014. Ezrin is down-regulated in diabetic kidney glomeruli and regulates actin reorganization and glucose uptake via GLUT1 in cultured podocytes. Am. J. Pathol. 184, 1727–1739. https://doi.org/10.1016/j.ajpath.2014.03.002

    Article  CAS  PubMed  Google Scholar 

  65. Kawasaki Y., Imaizumi T., Matsuura H., Ohara S., Takano K., Suyama K., Hashimoto K., Nozawa R., Suzuki H., Hosoya M. 2008. Renal expression of alpha-smooth muscle actin and c-Met in children with Henoch-Schönlein purpura nephritis. Pediatr. Nephrol. 23, 913–919. https://doi.org/10.1007/s00467-008-0749-6

    Article  PubMed  Google Scholar 

  66. Ren X., Guan G., Liu G., Liu G. 2009. Irbesartan ameliorates diabetic nephropathy by reducing the expression of connective tissue growth factor and alpha-smooth-muscle actin in the tubulointerstitium of diabetic rats. Pharmacology. 83, 80–87. https://doi.org/10.1159/000180123

    Article  CAS  PubMed  Google Scholar 

  67. Carling D., Sanders M.J., Woods A. 2008. The regulation of AMP-activated protein kinase by upstream kinases. Int. J. Obes. (Lond).32 (Suppl. 4), S55–S59. https://doi.org/10.1038/ijo.2008.124

    Article  CAS  Google Scholar 

  68. Hardie D.G. 2014. AMPK-sensing energy while talking to other signaling pathways. Cell. Metab.20 (6), 939–952. https://doi.org/10.1016/j.cmet.2014.09.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Steinberg G.R., Carling D. 2019. AMP-activated protein kinase: The current landscape for drug development. Nat. Rev. Drug Discov.18 (7), 527–551. https://doi.org/10.1038/s41573-019-0019-2

    Article  CAS  PubMed  Google Scholar 

  70. Yan Y., Zhou X.E., Xu H.E., Melcher K. 2018. Structure and physiological regulation of AMPK. Int. J. Mol. Sci. 19 (11), E3534. https://doi.org/10.3390/ijms19113534

    Article  CAS  PubMed  Google Scholar 

  71. Tanaka Y., Kume S., Kitada M., Kanasaki K., Uzu T., Maegawa H., Koya D. 2012. Autophagy as a therapeutic target in diabetic nephropathy. Exp. Diabetes Res. 2012, 628978. https://doi.org/10.1155/2012/628978

  72. Sharma K., RamachandraRao S., Qiu G., Usui H.K., Zhu Y., Dunn S.R., Ouedraogo R., Hough K., McCue P., Chan L., Falkner B., Goldstein B.J. 2008. Adiponectin regulates albuminuria and podocyte function in mice. J. Clin. Invest. 118 (5), 1645–1656. https://doi.org/10.1172/JCI32691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Joshi T., Singh A.K., Haratipour P., Sah A.N., Pandey A.K., Naseri R., Juyal V., Farzaei M.H. 2019. Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications. J. Cell. Physiol. 234 (10), 17212–17231. https://doi.org/10.1002/jcp.28528

    Article  CAS  PubMed  Google Scholar 

  74. Eisenreich A., Leppert U. 2017. Update on the protective renal effects of metformin in diabetic nephropathy. Curr. Med. Chem. 24 (31), 3397–3412. https://doi.org/10.2174/0929867324666170404143102

    Article  CAS  PubMed  Google Scholar 

  75. Corremans R., Vervaet B.A., D’Haese P.C., Neven E., Verhulst A. 2018. Metformin: A candidate drug for renal diseases. Int. J. Mol. Sci. 20 (1), pii: E42. https://doi.org/10.3390/ijms20010042

    Article  CAS  PubMed  Google Scholar 

  76. Blattner S.M., Hodgin J.B., Nishio M., Wylie S.A., Saha J., Soofi A.A., Vining C., Randolph A., Herbach N., Wanke R., Atkins K.B., Gyung Kang H., Henger A., Brakebusch C., Holzman L.B., Kretzler M. 2013. Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 84 (5), 920–930. https://doi.org/10.1038/ki.2013.175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Schell C., Huber T.B. 2017. The evolving complexity of the podocyte cytoskeleton. J. Am. Soc. Nephrol. 28 (11), 3166–3174. https://doi.org/10.1681/ASN.2017020143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yu S.M., Nissaisorakarn P., Husain I., Jim B. 2018. Proteinuric kidney diseases: A podocyte’s slit diaphragm and cytoskeleton approach. Front. Med. (Lausanne). 5, 221. https://doi.org/10.3389/fmed.2018.00221

    Article  Google Scholar 

  79. Ishizaka M., Gohda T., Takagi M., Omote K., Sonoda Y., Oliva Trejo J.A., Asao R., Hidaka T., Asanuma K., Horikoshi S., Tomino Y. 2015. Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice. Biochem. Biophys. Res. Commun. 467 (3), 549–555. https://doi.org/10.1016/j.bbrc.2015.09.158

    Article  CAS  PubMed  Google Scholar 

  80. Asao R., Seki T., Takagi M., Yamada H., Kodama F., Hosoe-Nagai Y., Tanaka E., Trejo J.A.O., Yamamoto-Nonaka K., Sasaki Y., Hidaka T., Ueno T., Yanagita M., Suzuki Y., Tomino Y., Asanuma K. 2018. Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis. Sci. Rep. 8 (1), 5061. https://doi.org/10.1038/s41598-018-23278-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Huang Z., Zhang L., Chen Y., Zhang H., Yu C., Zhou F., Zhang Z., Jiang L., Li R., Ma J., Li Z., Lai Y., Lin T., Zhao X., Zhang Q., Zhang B., Ye Z., Liu S., Wang W., Liang X., Liao R., Shi W. 2016. RhoA deficiency disrupts podocyte cytoskeleton and induces podocyte apoptosis by inhibiting YAP/dendrin signal. BMC Nephrol. 17 (1), 66. https://doi.org/10.1186/s12882-016-0287-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kistler A.D., Altintas M.M., Reiser J. 2012. Podocyte GTPases regulate kidney filter dynamics. Kidney Int. 81 (11), 1053–1055. https://doi.org/10.1038/ki.2012.12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Komers R. 2013. Rho kinase inhibition in diabetic kidney disease. Br. J. Clin. Pharmacol. 76 (4), 551–559. https://doi.org/10.1111/bcp.12196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Matoba K., Kawanami D., Nagai Y., Takeda Y., Akamine T., Ishizawa S., Kanazawa Y., Yokota T., Utsunomiya K. 2017. Rho-kinase blockade attenuates podocyte apoptosis by nnhibiting the Notch signaling pathway in diabetic nephropathy. Int. J. Mol. Sci. 18 (8), pii: E1795. https://doi.org/10.3390/ijms18081795

    Article  CAS  PubMed  Google Scholar 

  85. Peng F., Wu D., Gao B., Ingram A.J., Zhang B. 2008. RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes. 57 (6), 1683–1692. https://doi.org/10.2337/db07-1149

    Article  CAS  PubMed  Google Scholar 

  86. Zhu L., Jiang R., Aoudjit L., Jones N., Takano T. 2011. Activation of RhoA in podocytes induces focal segmental glomerulosclerosis. J. Am. Soc. Nephrol. 22 (9), 1621–1630. https://doi.org/10.1681/ASN.2010111146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lv Z., Hu M., Ren X., Fan M., Zhen J., Chen L., Lin J., Ding N., Wang Q., Wang R. 2016. Fyn mediates high glucose-induced actin cytoskeleton reorganization of podocytes via promoting ROCK activation in vitro.J. Diabetes Res. 2016, 5671803. https://doi.org/10.1155/2016/5671803

  88. Lin J.S., Susztak K. 2016. Podocytes: The weakest link in diabetic kidney disease? Curr. Diab. Rep. 16 (5), 45. https://doi.org/10.1007/s11892-016-0735-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Rao J., Ye Z., Tang H., Wang C., Peng H., Lai W., Li Y., Huang W., Lou T. 2017. The RhoA/ROCK pathway ameliorates adhesion and inflammatory infiltration induced by AGEs in glomerular endothelial cells. Sci. Rep. 7, 39727. https://doi.org/10.1038/srep39727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang W., Wang Y., Long J., Wang J., Haudek S.B., Overbeek P., Chang B.H., Schumacker P.T., Danesh F.R. 2012. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab. 15 (2), 186–200. https://doi.org/10.1016/j.cmet.2012.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Lin J.S., Shi Y., Peng H., Shen X., Thomas S., Wang Y., Truong L.D., Dryer S.E., Hu Z., Xu J. 2015. Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy. J. Pathol. 236 (1), 30–40. https://doi.org/10.1002/path.4508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhou J., Jia L., Hu Z., Wang Y. 2017. Pharmacological inhibition of PTEN aggravates acute kidney injury. Sci Rep. 7 (1), 9503. https://doi.org/10.1038/s41598-017-10336-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang H., Feng Z., Xie J., Wen F., Jv M., Liang T., Li J., Wang Y., Zuo Y., Li S., Li R., Li Z., Zhang B., Liang X., Liu S., Shi W., Wang W. 2018. Podocyte-specific knockin of PTEN protects kidney from hyperglycemia. Am. J. Physiol. Renal Physiol. 314 (6), F1096–F1107. https://doi.org/10.1152/ajprenal.00575.2017

    Article  CAS  PubMed  Google Scholar 

  94. Buvall L., Rashmi P., Lopez-Rivera E., Andreeva S., Weins A., Wallentin H., Greka A., Mundel P. 2013. Proteasomal degradation of Nck1 but not Nck2 regulates RhoA activation and actin dynamics. Nat. Commun. 4, 2863. https://doi.org/10.1038/ncomms3863

    Article  CAS  PubMed  Google Scholar 

  95. Elvin J., Buvall L., Lindskog Jonsson A., Granqvist A., Lassén E., Bergwall L., Nyström J., Haraldsson B. 2016. Melanocortin 1 receptor agonist protects podocytes through catalase and RhoA activation. Am. J. Physiol. Renal Physiol. 310 (9), F846–F856. https://doi.org/10.1152/ajprenal.00231.2015

    Article  CAS  PubMed  Google Scholar 

  96. Sun H., Schlondorff J., Higgs H.N., Pollak M.R. 2013. Inverted formin 2 regulates actin dynamics by antagonizing Rho/diaphanous-related formin signaling. J. Am. Soc. Nephrol. 24 (6), 917–929. https://doi.org/10.1681/ASN.2012080834

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Subramanian B., Sun H., Yan P., Charoonratana V.T., Higgs H.N., Wang F., Lai K.V., Valenzuela D.M., Brown E.J., Schlöndorff J.S., Pollak M.R. 2016. Mice with mutant Inf2 show impaired podocyte and slit diaphragm integrity in response to protamine-induced kidney injury. Kidney Int. 90 (2), 363–372. https://doi.org/10.1016/j.kint.2016.04.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhang Y., Xia H., Ge X., Chen Q., Yuan D., Leng W., Chen L., Tang Q., Bi F. 2014. CD44 acts through RhoA to regulate YAP signaling. Cell. Signal. 26 (11), 2504–2513. https://doi.org/10.1016/j.cellsig.2014.07.031

    Article  CAS  PubMed  Google Scholar 

  99. Schwartzman M., Reginensi A., Wong J.S., Basgen J.M., Meliambro K., Nicholas S.B., D’Agati V., McNeill H., Campbell K.N. 2015. Podocyte-specific deletion of Yes-associated protein causes FSGS and progressive renal failure. J. Am. Soc. Nephrol. 27 (1), 216–226. https://doi.org/10.1681/ASN.2014090916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Bonse J., Wennmann D.O., Kremerskothen J., Weide T., Michgehl U., Pavenstädt H., Vollenbröker B. 2018. Nuclear YAP localization as a key regulator of podocyte function. Cell Death Dis. 9 (9), 850. https://doi.org/10.1038/s41419-018-0878-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Meliambro K., Wong J.S., Ray J., Calizo R.C., Towne S., Cole B., El Salem F., Gordon R.E., Kaufman L., He J.C., Azeloglu E.U., Campbell K.N. 2017. The Hippo pathway regulator KIBRA promotes podocyte injury by inhibiting YAP signaling and disrupting actin cytoskeletal dynamics. J. Biol. Chem. 292 (51), 21137–21148. https://doi.org/10.1074/jbc.M117.819029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim E.Y., Alvarez-Baron C.P., Dryer S.E. 2009. Canonical transient receptor potential channel (TRPC)3 and TRPC6 associate with large-conductance Ca2+-activated K+ (BKCa) channels: Role in BKCa trafficking to the surface of cultured podocytes. Mol. Pharmacol. 75 (3), 466–477. https://doi.org/10.1124/mol.108.051912

    Article  CAS  PubMed  Google Scholar 

  103. Tian D., Jacobo S.M., Billing D., Rozkalne A., Gage S.D., Anagnostou T., Pavenstadt H., Hsu H.H., Schlondorff J., Ramos A., Greka A. 2010. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci. Signal. 3 (145), ra77. https://doi.org/10.1126/scisignal.2001200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Greka A., Mundel P. 2011. Balancing calcium signals through TRPC5 and TRPC6 in podocytes. J. Am. Soc. Nephrol. 22 (11), 1969–1980. https://doi.org/10.1681/ASN.2011040370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Mottl A.K., Lu M., Fine C.A., Weck K.E. 2013. A novel TRPC6 mutation in a family with podocytopathy and clinical variability. BMC Nephrol. 14, 104. https://doi.org/10.1186/1471-2369-14-104

    Article  PubMed  PubMed Central  Google Scholar 

  106. Schaldecker T., Kim S., Tarabanis C., Tian D., Hakroush S., Castonguay P., Ahn W., Wallentin H., Heid H., Hopkins C.R., Lindsley C.W., Riccio A., Buvall L., Weins A., Greka A. 2013. Inhibition of the TRPC5 ion channel protects the kidney filter. J. Clin. Invest. 123 (12), 5298–5309. https://doi.org/10.1172/JCI71165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ilatovskaya D.V., Palygin O., Chubinskiy-Nadezhdin V., Negulyaev Y.A., Ma R., Birnbaumer L., Staruschenko A. 2014. Angiotensin II has acute effects on TRPC6 channels in podocytes of freshly isolated glomeruli. Kidney Int. 86 (3), 506–514. https://doi.org/10.1038/ki.2014.71

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Ilatovskaya D.V., Levchenko V., Lowing A., Shuyskiy L.S., Palygin O., Staruschenko A. 2015. Podocyte injury in diabetic nephropathy: Implications of angiotensin II-dependent activation of TRPC channels. Sci. Rep. 5, 17637. https://doi.org/10.1038/srep17637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ilatovskaya D.V., Staruschenko A. 2015. TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases. Am. J. Physiol. Renal Physiol. 309 (5), F393–F397. https://doi.org/10.1152/ajprenal.00186.2015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhou Y., Castonguay P., Sidhom E.H., Clark A.R., Dvela-Levitt M., Kim S., Sieber J., Wieder N., Jung J.Y., Andreeva S., Reichardt J., Dubois F., Hoffmann S.C., Basgen J.M., Montesinos M.S., Weins A., Johnson A.C., Lander E.S., Garrett M.R., Hopkins C.R., Greka A. 2017. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science. 358 (6368), 1332–1336. https://doi.org/10.1126/science.aal4178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Staruschenko A., Spires D., Palygin O. 2019. Role of TRPC6 in progression of diabetic kidney disease. Curr. Hypertens. Rep. 21 (7), 48. https://doi.org/10.1007/s11906-019-0960-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Ilatovskaya D.V., Blass G., Palygin O., Levchenko V., Pavlov T.S., Grzybowski M.N., Winsor K., Shuyskiy L.S., Geurts A.M., Cowley A.W.Jr., Birnbaumer L., Staruschenko A. 2018. A NOX4/TRPC6 pathway in podocyte calcium regulation and renal damage in diabetic Kidney disease. J. Am. Soc. Nephrol. 29 (7), 1917–1927. https://doi.org/10.1681/ASN.2018030280

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Spires D., Ilatovskaya D.V., Levchenko V., North P.E., Geurts A.M., Palygin O., Staruschenko A. 2018. Protective role of Trpc6 knockout in the progression of diabetic kidney disease. Am. J. Physiol. Renal Physiol.315 (4), F1091–F1097. https://doi.org/10.1152/ajprenal.00155.2018

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Spires D., Manis A.D., Staruschenko A. 2019. Ion channels and transporters in diabetic kidney disease. Curr. Top. Membr. 83, 353–396. https://doi.org/10.1016/bs.ctm.2019.01.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rohacs T. 2013. Regulation of transient receptor potential channels by the phospholipase C pathway. Adv. Biol. Regul. 53 (3), 341–355. https://doi.org/10.1016/j.jbior.2013.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Ilatovskaya D.V., Palygin O., Levchenko V., Endres B.T., Staruschenko A. 2017. The role of angiotensin II in glomerular volume dynamics and podocyte calcium handling. Sci. Rep. 7 (1), 299. https://doi.org/10.1038/s41598-017-00406-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Kalwa H., Storch U., Demleitner J., Fiedler S., Mayer T., Kannler M., Fahlbusch M., Barth H., Smrcka A., Hildebrandt F., Gudermann T., Dietrich A. 2015. Phospholipase C epsilon (PLCε) induced TRPC6 activation: A common but redundant mechanism in primary podocytes. J. Cell. Physiol. 230 (6), 1389–1399. https://doi.org/10.1002/jcp.24883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Staruschenko A. 2019. TRPC6 in diabetic kidney disease: Good guy or bad guy? Kidney Int. 95 (2), 256–258. https://doi.org/10.1016/j.kint.2018.10.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Smrcka A.V., Brown J.H., Holz G.G. 2012. Role of phospholipase Cε in physiological phosphoinositide signaling networks. Cell. Signal. 24 (6), 1333–1343. https://doi.org/10.1016/j.cellsig.2012.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Nogueira A., Pires M.J., Oliveira P.A. 2017. Pathophysiological mechanisms of renal fibrosis: A review of animal models and therapeutic strategies. In Vivo. 31 (1), 1–22. https://doi.org/10.21873/invivo.11019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sanz A.B., Ramos A.M., Soler M.J., Sanchez-Niño M.D., Fernandez-Fernandez B., Perez-Gomez M.V., Ortega M.R., Alvarez-Llamas G., Ortiz A. 2019. Advances in understanding the role of angiotensin-regulated proteins in kidney diseases. Expert. Rev. Proteomics. 16 (1), 77–92. https://doi.org/10.1080/14789450.2018.1545577

    Article  CAS  PubMed  Google Scholar 

  122. Sharma R., Sharma M., Vamos S., Savin V.J., Wiegmann T.B. 2001. Both subtype 1 and 2 receptors of angiotensin II participate in regulation of intracellular calcium in glomerular epithelial cells. J. Lab. Clin. Med. 138, 40–49. https://doi.org/10.1067/mlc.2001.115493

    Article  CAS  PubMed  Google Scholar 

  123. Fukuda A., Fujimoto S., Iwatsubo S., Kawachi H., Kitamura K. 2010. Effects of mineralocorticoid and angiotensin II receptor blockers on proteinuria and glomerular podocyte protein expression in a model of minimal change nephrotic syndrome. Nephrology. 15 (3), 321–326. https://doi.org/10.1111/j.1440-1797.2009.01256.x

    Article  CAS  PubMed  Google Scholar 

  124. Nijenhuis T., Sloan A.J., Hoenderop J.G., Flesche J., van Goor H., Kistler A.D., Bakker M., Bindels R.J., de Boer R.A., Moller C.C., Hamming I., Navis G., Wetzels J.F., Berden J.H., Reiser J., Faul C., van der Vlag J. 2011. Angiotensin II contributes to podocyte injury by increasing TRPC6 expression via an NFAT-mediated positive feedback signaling pathway. Am. J. Pathol. 179 (4), 1719–1732. https://doi.org/10.1016/j.ajpath.2011.06.033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yu Y., Zhang L., Xu G., Wu Z., Li Q., Gu Y., Niu J. 2018. Angiotensin II type I receptor agonistic autoantibody induces podocyte injury via activation of the TRPC6-calcium/calcineurin pathway in pre-eclampsia. Kidney Blood Press Res. 43 (5), 1666–1676. https://doi.org/10.1159/000494744

    Article  CAS  PubMed  Google Scholar 

  126. Nitschke R., Henger A., Ricken S., Gloy J., Müller V., Greger R., Pavenstädt H. 2000. Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus. Kidney Int. 57, 41–49. https://doi.org/10.1046/j.1523-1755.2000.00810.x

    Article  CAS  PubMed  Google Scholar 

  127. Kim E.Y., Anderson M., Wilson C., Hagmann H., Benzing T., Dryer S.E. 2013. NOX2 interacts with podocyte TRPC6 channels and contributes to their activation by diacylglycerol: Essential role of podocin in formation of this complex. Am. J. Physiol. Cell. Physiol. 305 (9), C960–C971. https://doi.org/10.1152/ajpcell.00191.2013

    Article  CAS  PubMed  Google Scholar 

  128. Yang Q., Wu F.R., Wang J.N., Gao L., Jiang L., Li H.D., Ma Q., Liu X.Q., Wei B., Zhou L., Wen J., Ma T.T., Li J., Meng X.M. 2018. Nox4 in renal diseases: An update. Free Radic. Biol. Med. 124, 466–472. https://doi.org/10.1016/j.freeradbiomed.2018.06.042

    Article  CAS  PubMed  Google Scholar 

  129. Gorin Y., Wauquier F. 2015. Upstream regulators and downstream effectors of NADPH oxidases as novel therapeutic targets for diabetic kidney disease. Mol. Cells. 38 (4), 285–296. https://doi.org/10.14348/molcells.2015.0010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chiluiza D., Krishna S., Schumacher V.A., Schlondorff J. 2013. Gain-of-function mutations in transient receptor potential C6 (TRPC6) activate extracellular signal-regulated kinases 1/2 (ERK1/2). J. Biol. Chem. 288 (25), 18407–18420. https://doi.org/10.1074/jbc.M113.463059

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zhang H., Ding J., Fan Q., Liu S. 2009. TRPC6 up-regulation in Ang II-induced podocyte apoptosis might result from ERK activation and NF-kappaB translocation. Exp. Biol. Med. 234 (9), 1029–1036. https://doi.org/10.3181/0901-RM-11

    Article  CAS  Google Scholar 

  132. Riccardi D., Valenti G. 2016. Localization and function of the renal calcium-sensing receptor. Nat. Rev. Nephrol. 12 (7), 414–425. https://doi.org/10.1038/nrneph.2016.59

    Article  CAS  PubMed  Google Scholar 

  133. Meng K., Xu J., Zhang C., Zhang R., Yang H., Liao C., Jiao J. 2014. Calcium sensing receptor modulates extracellular calcium entry and proliferation via TRPC3/6 channels in cultured human mesangial cells. PLoS One. 9 (6), e98777. https://doi.org/10.1371/journal.pone.0098777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zhang L., Ji T., Wang Q., Meng K., Zhang R., Yang H., Liao C., Ma L., Jiao J. 2017. Calcium-sensing receptor stimulation in cultured glomerular podocytes induces TRPC6-dependent calcium entry and RhoA activation. Cell. Physiol. Biochem. 43 (5), 1777–1789. https://doi.org/10.1159/000484064

    Article  CAS  PubMed  Google Scholar 

  135. Gorvin C.M., Babinsky V.N., Malinauskas T., Nissen P.H., Schou A.J., Hanyaloglu A.C., Siebold C., Jones E.Y., Hannan F.M., Thakker R.V. 2018. A calcium-sensing receptor mutation causing hypocalcemia disrupts a transmembrane salt bridge to activate β-arrestin-biased signaling. Sci. Signal. 11 (518), eaan3714. https://doi.org/10.1126/scisignal.aan3714

  136. Mos I., Jacobsen S.E., Foster S.R., Bräuner-Osborne H. 2019. Calcium-sensing receptor internalization is β-arrestin-dependent and modulated by allosteric ligands. Mol. Pharmacol. 96 (4), 463–474. https://doi.org/10.1124/mol.119.116772

    Article  CAS  PubMed  Google Scholar 

  137. Waasdorp M., Duitman J., Florquin S., Spek C.A. 2016. Protease-activated receptor-1 deficiency protects against streptozotocin-induced diabetic nephropathy in mice. Sci. Rep. 6, 33030. https://doi.org/10.1038/srep33030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Sharma R., Waller A.P., Agrawal S., Wolfgang K.J., Luu H., Shahzad K., Isermann B., Smoyer W.E., Nieman M.T., Kerlin B.A. 2017. Thrombin-induced podocyte injury is protease-activated receptor dependent. J. Am. Soc. Nephrol. 28 (9), 2618–2630. https://doi.org/10.1681/ASN.2016070789

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Svenningsen P., Hinrichs G.R., Zachar R., Ydegaard R., Jensen B.L. 2017. Physiology and pathophysiology of the plasminogen system in the kidney. Pflugers Arch. 469 (11), 1415–1423. https://doi.org/10.1007/s00424-017-2014-y

    Article  CAS  PubMed  Google Scholar 

  140. Cunningham M.A., Rondeau E., Chen X., Coughlin S.R., Holdsworth S.R., Tipping P.G. 2000. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J. Exp. Med. 191 (3), 455–462. https://doi.org/10.1084/jem.191.3.455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Palygin O., Ilatovskaya D.V., Staruschenko A. 2016. Protease-activated receptors in kidney disease progression. Am. J. Physiol. Renal Physiol. 311 (6), F1140–F1144. https://doi.org/10.1152/ajprenal.00460.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Ay L., Hoellerl F., Ay C., Brix J.M., Koder S., Schernthaner G.H., Pabinger I., Schernthaner G. 2012. Thrombin generation in type 2 diabetes with albuminuria and macrovascular disease. Eur. J. Clin. Invest. 42 (5), 470–477. https://doi.org/10.1111/j.1365-2362.2011.02602.x

    Article  CAS  PubMed  Google Scholar 

  143. Konieczynska M., Fil K., Bazanek M., Undas A. 2014. Prolonged duration of type 2 diabetes is associated with increased thrombin generation, prothrombotic fibrin clot phenotype and impaired fibrinolysis. Thromb. Haemost. 111 (4), 685–693. https://doi.org/10.1160/TH13-07-0566

    Article  CAS  PubMed  Google Scholar 

  144. Sakai T., Nambu T., Katoh M., Uehara S., Fukuroda T., Nishikibe M. 2009. Up-regulation of protease-activated receptor-1 in diabetic glomerulosclerosis. Biochem. Biophys. Res. Commun. 384, 173–179. https://doi.org/10.1016/j.bbrc.2009.04.105

    Article  CAS  PubMed  Google Scholar 

  145. Lin H., Liu A.P., Smith T.H., Trejo J. 2013. Cofactoring and dimerization of proteinase-activated receptors. Pharmacol. Rev. 65 (4), 1198–1213. https://doi.org/10.1124/pr.111.004747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Madhusudhan T., Kerlin B.A., Isermann B. 2016. The emerging role of coagulation proteases in kidney disease. Nat. Rev. Nephrol. 12 (2), 94–109. https://doi.org/10.1038/nrneph.2015.177

    Article  CAS  PubMed  Google Scholar 

  147. Li H., Wang Y., Zhou Z., Tian F., Yang H., Yan J. 2019. Combination of leflunomide and benazepril reduces renal injury of diabetic nephropathy rats and inhibits high-glucose induced cell apoptosis through regulation of NF-κB, TGF-β and TRPC6. Ren. Fail. 41 (1), 899–906. https://doi.org/10.1080/0886022X.2019.1665547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Kuang X., Zhou Q., Li Z., Hu Y., Kang Y., Huang W. 2019. –254C>G SNP in the TRPC6 gene promoter influences its expression via interaction with the NF-κB subunit RELA in steroid-resistant nephrotic syndrome children. Int. J. Genomics. 2019, 2197837. https://doi.org/10.1155/2019/2197837

  149. Liu Y. 2004. Epithelial to mesenchymal transition in renal fibrogenesis: Pathologic significance molecular mechanism, and therapeutic intervention. J. Am. Soc. Nephrol. 15 (1), 1–12. https://doi.org/10.1097/01.asn.0000106015.29070.e7

    Article  CAS  PubMed  Google Scholar 

  150. Zhao L., Chi L., Zhao J., Wang X., Chen Z., Meng L., Liu G., Guan G., Wang F. 2016. Serum response factor provokes epithelial-mesenchymal transition in renal tubular epithelial cells of diabetic nephropathy. Physiol. Genomics. 48 (8), 580–588. https://doi.org/10.1152/physiolgenomics.00058.2016

    Article  CAS  PubMed  Google Scholar 

  151. Thiery J.P., Sleeman J.P. 2006. Complex networks orchestrate epithelial-mesenchymal transitions. Nat. Rev. Mol. Cell Biol. 7 (2), 131–142. https://doi.org/10.1038/nrm1835

    Article  CAS  PubMed  Google Scholar 

  152. Loeffler I., Wolf G. 2015. Epithelial-to-mesenchymal transition in diabetic nephropathy: Fact or fiction? Cell. 4 (4), 631–652. https://doi.org/10.3390/cells4040631

    Article  Google Scholar 

  153. Dai H.Y., Zheng M., Tang R.N., Ni J., Ma K.L., Li Q., Liu B.C. 2011. Effects of angiotensin receptor blocker on phenotypic alterations of podocytes in early diabetic nephropathy. Am. J. Med. Sci. 341 (3), 207–214. https://doi.org/10.1097/MAJ.0b013e3182010da9

    Article  PubMed  Google Scholar 

  154. Yamaguchi Y., Iwano M., Suzuki D., Nakatani K., Kimura K., Harada K., Kubo A., Akai Y., Toyoda M., Kanauchi M., Neilson E.G., Saito Y. Epithelial-mesenchymal transition as a potential explanation for podocyte depletion in diabetic nephropathy. Am. J. Kidney Dis. 54 (4), 653–664. https://doi.org/10.1053/j.ajkd.2009.05.009

  155. Li Y., Kang Y.S., Dai C., Kiss L.P., Wen X., Liu Y. 2008. Epithelial-to-mesenchymal transition is a potential pathway leading to podocyte dysfunction and proteinuria. Am. J. Pathol.172 (2), 299–308. https://doi.org/10.2353/ajpath.2008.070057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Sun L.N., Chen Z.X., Liu X.C., Liu H.Y., Guan G.J., Liu G. 2014. Curcumin ameliorates epithelial-to-mesenchymal transition of podocytes in vivo and in vitro via regulating caveolin-1. Biomed. Pharmacother. 68 (8), 1079–1088. https://doi.org/10.1016/j.biopha.2014.10.005

    Article  CAS  PubMed  Google Scholar 

  157. Xing L., Liu Q., Fu S., Li S., Yang L., Liu S., Hao J., Yu L., Duan H. 2015. PTEN inhibits high glucose-induced phenotypic transition in podocytes. J. Cell. Biochem. 116 (8), 1776–1784. https://doi.org/10.1002/jcb.25136

    Article  CAS  PubMed  Google Scholar 

  158. Ying Q., Wu G. 2017. Molecular mechanisms involved in podocyte EMT and concomitant diabetic kidney diseases: An update. Ren. Fail. 39 (1), 474–483. https://doi.org/10.1080/0886022X.2017.1313164

    Article  PubMed  PubMed Central  Google Scholar 

  159. Stacy A.J., Craig M.P., Sakaram S., Kadakia M. 2017. ΔNp63α and microRNAs: Leveraging the epithelial-mesenchymal transition. Oncotarget. 8 (2), 2114–2129. https://doi.org/10.18632/oncotarget.13797

    Article  PubMed  Google Scholar 

  160. Srivastava S.P., Hedayat F.A., Kanasaki K., Goodwin J.E. 2019. microRNA crosstalk influences epithelial-to-mesenchymal, endothelial-to-mesenchymal, and macrophage-to-mesenchymal transitions in the kidney. Front. Pharmacol.10, 904. https://doi.org/10.3389/fphar.2019.00904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Niu H., Nie L., Liu M., Chi Y., Zhang T., Li Y. 2014. Benazepril affects integrin-linked kinase and smooth muscle α-actin expression in diabetic rat glomerulus and cultured mesangial cells. BMC Nephrol. 15, 1–10. https://doi.org/10.1186/1471-2369-15-135

    Article  CAS  Google Scholar 

  162. Li L., Chen L., Zang J., Tang X., Liu Y., Zhang J., Bai L., Yin Q., Lu Y., Cheng J., Fu P., Liu F. 2015. C3a and C5a receptor antagonists ameliorate endothelial-myofibroblast transition via the Wnt/β-catenin signaling pathway in diabetic kidney disease. Metabolism. 64 (5), 597–610. https://doi.org/10.1016/j.metabol.2015.01.014

    Article  CAS  PubMed  Google Scholar 

  163. Shi G., Wu W., Wan Y.G., Hex H.W., Tu Y., Han W.B., Liu B.H., Liu Y.L., Wan Z.Y. 2018. Low dose of triptolide ameliorates podocyte epithelial-mesenchymal transition induced by high dose of D-glucose via inhibiting Wnt3α/β-catenin signaling pathway activation. Zhongguo Zhong Yao Za Zhi. 43 (1), 139–146. https://doi.org/10.19540/j.cnki.cjcmm.20171027.013

    Article  PubMed  Google Scholar 

  164. Guo J., Xia N., Yang L., Zhou S., Zhang Q., Qiao Y., Liu Z. 2014. GSK-3β and vitamin D receptor are involved in β-catenin and Snail signaling in high glucose-induced epithelial-mesenchymal transition of mouse podocytes. Cell. Physiol. Biochem. 33 (4), 1087–1096. https://doi.org/10.1159/000358678

    Article  CAS  PubMed  Google Scholar 

  165. Wan J., Li P., Liu D.W., Chen Y., Mo H.Z., Liu B.G., Chen W.J., Lu X.Q., Guo J., Zhang Q., Qiao Y.J., Liu Z.S., Wan G.R. 2016. GSK-3β inhibitor attenuates urinary albumin excretion in type 2 diabetic db/db mice, and delays epithelial-to-mesenchymal transition in mouse kidneys and podocytes. Mol. Med. Rep. 14 (2), 1771–1784. https://doi.org/10.3892/mmr.2016.5441

    Article  CAS  PubMed  Google Scholar 

  166. Paeng J., Chang J.H., Lee S.H., Nam B.Y., Kang H.Y., Kim S., Oh H.J., Park J.T., Han S.H., Yoo T.H., Kang S.W. 2014. Enhanced glycogen synthase kinase-3β activity mediates podocyte apoptosis under diabetic conditions. Apoptosis. 19 (12), 1678–1690. https://doi.org/10.1007/s10495-014-1037-5

    Article  CAS  PubMed  Google Scholar 

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ACKNOWLEDGMENTS

The work was supported by the Russian Science Foundation (project no. 19-14-00114).

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  1. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223, St. Petersburg, Russia

    A. O. Shpakov

  2. Cytology Institute of Russian Academy of Sciences, 194064, St. Petersburg, Russia

    E. V. Kaznacheyeva

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  1. A. O. Shpakov
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Correspondence to A. O. Shpakov.

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Translated by E. Makeeva

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Shpakov, A.O., Kaznacheyeva, E.V. Molecular Mechanisms of Apoptosis of Glomerular Podocytes in Diabetic Nephropathy. Biochem. Moscow Suppl. Ser. A 14, 205–222 (2020). https://doi.org/10.1134/S1990747820030058

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