684
Views
3
CrossRef citations to date
0
Altmetric
Review

Rho GTPases in kidney physiology and diseases

, , &
Pages 141-161 | Received 17 Jul 2020, Accepted 17 May 2021, Published online: 17 Jun 2021

References

  • Puelles VG, Hoy WE, Hughson MD, et al. Glomerular number and size variability and risk for kidney disease. Curr Opin Nephrol Hypertens. 2011;20:7–15.
  • Faul C, Asanuma K, Yanagida-Asanuma E, et al. Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends Cell Biol. 2007;17(9):428–437.
  • Haraldsson B, Nyström J. The glomerular endothelium: new insights on function and structure. Curr Opin Nephrol Hypertens. 2012;21(3):258–263.
  • Matsuda J, Asano-Matsuda K, Kitzler T, et al. Rho GTPase regulatory proteins in podocytes. Kidney Int. 2020;S0085-2538(20)31230–8. DOI:10.1016/j.kint.2020.08.035
  • Reiser J, Altintas MM. Podocytes. Version 1. F1000Res. 2016;5:F1000 Faculty Rev–114.
  • Scott RP, Quaggin SE. Review series: the cell biology of renal filtration. J Cell Biol. 2015;209(2):199–210.
  • Pavenstädt H, Kriz W, Kretzler M. Cell biology of the glomerular podocyte. Physiol Rev. 2003;83(1):253–307.
  • Castrop H. The role of renal interstitial cells in proximal tubular regeneration. Nephron Exp Nephrol Genet. 2019;141:265–272.
  • Bianchi F, Mattii L, D’Alessandro D, et al. Cellular and subcellular localization of the small G protein RhoA in the human and rat embryonic and adult kidney. Acta Histochem. 2003;105(1):89–97.
  • Boivin D, Béliveau R. Subcellular distribution and membrane association of Rho-related small GTP-binding proteins in kidney cortex. Am J Physiol. 1995;269(2 Pt 2):F180–9.
  • Nakagawa O, Fujisawa K, Ishizaki T, et al. ROCK-I and ROCK-II, two isoforms of Rho-associated coiled-coil forming protein serine/threonine kinase in mice. FEBS Lett. 1996;392(2):189–193.
  • Sladojevic N, Yu B, Liao JK. ROCK as a therapeutic target for ischemic stroke. Expert Rev Neurother. 2017;17(12):1167–1177.
  • Hayashi K, Wakino S, Kanda T, et al. Molecular mechanisms and therapeutic strategies of chronic renal injury: role of rho-kinase in the development of renal injury. J Pharmacol Sci. 2006;100(1):29–33.
  • Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 2006;16(10):522–529.
  • Knaus UG, Bokoch GM. The p21Rac/Cdc42-activated kinases (PAKs). Int J Biochem Cell Biol. 1998;30(8):857–862.
  • Conti S, Perico L, Grahammer F, et al. The long journey through renal filtration: new pieces in the puzzle of slit diaphragm architecture. Curr Opin Nephrol Hypertens. 2017;26(3):148–153.
  • Huber TB, Benzing T. The slit diaphragm: a signaling platform to regulate podocyte function. Curr Opin Nephrol Hypertens. 2005;14(3):211–216.
  • Reiser J, Kriz W, Kretzler M, et al. The glomerular slit diaphragm is a modified adherens junction. J Am Soc Nephrol. 2000;11(1):1–8.
  • Ruotsalainen V, Patrakka J, Tissari P, et al. Role of nephrin in cell junction formation in human nephrogenesis. Am J Pathol. 2000;157:1905–1916.
  • Yaoita E, Kurihara H, Yoshida Y, et al. Role of Fat1 in cell-cell contact formation of podocytes in puromycin aminonucleoside nephrosis and neonatal kidney. Kidney Int. 2005;68(2):542–551.
  • Fukasawa H, Bornheimer S, Kudlicka K, et al. Slit diaphragms contain tight junction proteins. J Am Soc Nephrol. 2009;20(7):1491–1503.
  • Saleem MA, Ni L, Witherden I, et al. Co-localization of nephrin, podocin, and the actin cytoskeleton: evidence for a role in podocyte foot process formation. Am J Pathol. 2002;161(4):1459–1466.
  • Tanoue T, Takeichi M. Mammalian Fat1 cadherin regulates actin dynamics and cell-cell contact. J Cell Biol. 2004;165(4):517–528.
  • Mundel P, Reiser J. Proteinuria: an enzymatic disease of the podocyte? Kidney Int. 2010;77:571–580.
  • Blattner SM, Hodgin JB, Nishio M, et al. Divergent functions of the Rho GTPases Rac1 and Cdc42 in podocyte injury. Kidney Int. 2013;84(5):920–930.
  • Scott RP, Hawley SP, Ruston J, et al. Podocyte-specific loss of Cdc42 leads to congenital nephropathy. J Am Soc Nephrol. 2012;23(7):1149–1154.
  • Robins R, Baldwin C, Aoudjit L, et al. Rac1 activation in podocytes induces the spectrum of nephrotic syndrome. Kidney Int. 2017;92:349–364.
  • Yu H, Suleiman H, Kim AHJ, et al. Rac1 activation in podocytes induces rapid foot process effacement and proteinuria. Mol Cell Biol. 2013;33(23):4755–4764.
  • Muraleedharan S, Sam A, Skaer H, et al. Networks that link cytoskeletal regulators and diaphragm proteins underpin filtration function in Drosophila nephrocytes. Exp Cell Res. 2018;364(2):234–242.
  • Burridge K, Doughman R. Front and back by Rho and Rac. Nat Cell Biol. 2006;8(8):781–782.
  • Asanuma K, Yanagida-Asanuma E, Faul C, et al. Synaptopodin orchestrates actin organization and cell motility via regulation of RhoA signalling. Nat Cell Biol. 2006;8(5):485–491.
  • Greka A, Mundel P. Cell biology and pathology of podocytes. Annu Rev Physiol. 2012;74(1):299–323.
  • Kistler AD, Altintas MM, Reiser J. Podocyte GTPases regulate kidney filter dynamics. Kidney Int. 2012;81(11):1053–1055.
  • Wang L, Ellis MJ, Gomez JA, et al. Mechanisms of the proteinuria induced by Rho GTPases. Kidney Int. 2012;81(11):1075–1085.
  • Huang Z, Zhang L, Chen Y, et al. RhoA deficiency disrupts podocyte cytoskeleton and induces podocyte apoptosis by inhibiting YAP/dendrin signal. BMC Nephrol. 2016b;17(1):66.
  • Bustelo XR. Vav family exchange factors: an integrated regulatory and functional view. Small GTPases. 2014;5(2):e973757.
  • Chan CY, Ng KH, Chen J, et al. Novel role of Vav1-Rac1 pathway in actin cytoskeleton regulation in interleukin-13-induced minimal change-like nephropathy. Clin Sci (Lond). 2016;130(24):2317–2327.
  • Sauzeau V, Sevilla MA, Rivas-Elena JV, et al. Vav3 proto-oncogene deficiency leads to sympathetic hyperactivity and cardiovascular dysfunction. Nat Med. 2006;12(7):841‐5.
  • Yu SM, Nissaisorakarn P, Husain I, et al. Proteinuric kidney diseases: a Podocyte’s slit diaphragm and cytoskeleton approach. Front Med (Lausanne). 2018;5:221.
  • Asao R, Seki T, Takagi M, et al. Rac1 in podocytes promotes glomerular repair and limits the formation of sclerosis. Sci Rep. 2018;8(1):5061.
  • Huang Z, Zhang L, Chen Y, et al. Cdc42 deficiency induces podocyte apoptosis by inhibiting the Nwasp/stress fibers/YAP pathway. Cell Death Dis. 2016a;7(3):e2142.
  • Mundel P, Heid HW, Mundel TM, et al. Synaptopodin: an actin-associated protein in telencephalic dendrites and renal podocytes. J Cell Biol. 1997;139:193–204.
  • Asanuma K, Kim K, Oh J, et al. Synaptopodin regulates the actin-bundling activity of α-actinin in an isoform-specific manner. J Clin Invest. 2005;115(5):1188–1198.
  • Yanagida-Asanuma E, Asanuma K, Kim K, et al. Synaptopodin protects against proteinuria by disrupting Cdc42: IRSp53:menasignaling complexes in kidney podocytes. Am J Pathol. 2007;171(2):415–427.
  • Kim EY, Suh JM, Chiu YH, et al. Regulation of podocyte BK Ca channels by synaptopodin, Rho, and actin microfilaments. Am J Physiol Renal Physiol. 2010;299(3):F594–604.
  • Buvall L, Wallentin H, Sieber J, et al. Synaptopodin is a coincidence detector of tyrosine versus Serine/Threonine phosphorylation for the modulation of Rho protein crosstalk in Podocytes. J Am Soc Nephrol. 2017;28(3):837–851.
  • Meyer-Schwesinger C, Dehde S, Sachs M, et al. Rho-kinase inhibition prevents proteinuria in immune-complex-mediated antipodocyte nephritis. Am J Physiol Renal Physiol. 2012;303(7):F1015–25.
  • Ilatovskaya DV, Staruschenko A. TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases. Am J Physiol Renal Physiol. 2015;309(5):F393–F397.
  • Tian D, Jacobo SM, Billing D, et al. Antagonistic regulation of actin dynamics and cell motility by TRPC5 and TRPC6 channels. Sci Signal. 2010;3(145):ra77.
  • Reiser J, Polu KR, Moller CC, et al. TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function. Nat Genet. 2005;37:739–744.
  • Winn MP, Conlon PJ, Lynn KL, et al. A mutation in the TRPC6 cation channel causes familial focal segmental glomerulosclerosis. Science. 2005;308(5729):1801–1804.
  • Bezzerides VJ, Ramsey IS, Kotecha S, et al. Rapid vesicular translocation and insertion of TRP channels. Nat Cell Biol. 2004;6(8):709–720.
  • Zhou Y, Castonguay P, Sidhom EH, et al. A small-molecule inhibitor of TRPC5 ion channels suppresses progressive kidney disease in animal models. Science. 2017;358(6368):1332–1336.
  • Wang X, Dande RR, Yu H, et al. TRPC5 does not cause or aggravate glomerular disease. J Am Soc Nephrol. 2018;29(2):409–415.
  • Watanabe G, Saito Y, Madaule P, et al. Protein kinase N (PKN) and PKN-related protein rhophilin as targets of small GTPase Rho. Science. 1996;271(5249):645–648.
  • Lal MA, Andersson AC, Katayama K, et al. Rhophilin-1 is a key regulator of the podocyte cytoskeleton and is essential for glomerular filtration. J Am Soc Nephrol. 2015;26(3):647–662.
  • Yang JW, Dettmar AK, Kronbichler A, et al. Recent advances of animal model of focal segmental glomerulosclerosis. Clin Exp Nephrol. 2018;22(4):752–763.
  • Schlondorff D, Banas B. The mesangial cell revisited: no cell is an Island. J Am Soc Nephrol. 2009;20(6):1179–1187.
  • Stockand JD, Sansom SC. Glomerular mesangial cells: electrophysiology and regulation of contraction. Physiol Rev. 1998;78:723–744.
  • Giehl K, Graness A, Goppelt-Struebe M. The small GTPase Rac-1 is a regulator of mesangial cell morphology and thrombospondin-1 expression. Am J Physiol Renal Physiol. 2008;294(2):F407–13.
  • Floege J, Johnson RJ, Couser WG. Mesangial cells in the pathogenesis of progressive glomerular disease in animal models. Clin Investig. 1992;70(9):857–864.
  • Scindia YM, Deshmukh US, Bagavant H. Mesangial pathology in glomerular disease: targets for therapeutic intervention. Adv Drug Deliv Rev. 2010;62:1337–1343.
  • Anders HJ, Vielhauer V, Schlondorff D. Chemokines and chemokine receptors are involved in the resolution or progression of renal disease. Kidney Int. 2003;63(2):401–415.
  • Matoba K, Kawanami D, Ishizawa S, et al. Rho-kinase mediates TNF-α-induced MCP-1 expression via p38 MAPK signaling pathway in mesangial cells. Biochem Biophys Res Commun. 2010;402(4):725–730.
  • Ichimura K, Kurihara H, Sakai T. Primary cilia disappear in rat podocytes during glomerular development. Cell Tissue Res. 2010;341(1):197–209.
  • Wang S, Dong Z. Primary cilia and kidney injury: current research status and future perspectives. Am J Physiol Renal Physiol. 2013;305(8):F1085–98.
  • Elias BC, Das A, Parekh DV, et al. Cdc42 regulates epithelial cell polarity and cytoskeletal function during kidney tubule development. J Cell Sci. 2015;128(23):4293–4305.
  • Zuo X, Fogelgren B, Lipschutz JH. The small GTPase Cdc42 is necessary for primary ciliogenesis in renal tubular epithelial cells. J Biol Chem. 2011;286(25):22469–22477.
  • Choi SY, Chacon-Heszele MF, Huang L, et al. Cdc42 deficiency causes ciliary abnormalities and cystic kidneys. J Am Soc Nephrol. 2013;24(9):1435–1450.
  • Baek JI, Kwon SH, Zuo X, et al. Dynamin binding protein (Tuba) deficiency inhibits ciliogenesis and nephrogenesis in Vitro and in Vivo. J Biol Chem. 2016;291(16):8632–8643.
  • Zhao B, Lei QY, Guan KL. The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Curr Opin Cell Biol. 2008;20(6):638–646.
  • Wennmann DO, Vollenbröker B, Eckart AK, et al. The Hippo pathway is controlled by Angiotensin II signaling and its reactivation induces apoptosis in podocytes. Cell Death Dis. 2014;5(11):e1519.
  • Reginensi A, Scott RP, Gregorieff A, et al. Yap- and Cdc42-dependent nephrogenesis and morphogenesis during mouse kidney development. PLoS Genet. 2013;9(3):e1003380.
  • Gee HY, Sadowski CE, Aggarwal PK, et al. FAT1 mutations cause a glomerulotubular nephropathy. Nat Commun. 2016;7(1):10822.
  • Mack NA, Georgiou M. The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases. 2014;5(2):1–16.
  • Raman N, Atkinson SJ. Rho controls actin cytoskeletal assembly in renal epithelial cells during ATP depletion and recovery. Am J Physiol. 1999;276:C1312–24.
  • Garty H, Palmer LG. Epithelial sodium channels: function, structure, and regulation. Physiol Rev. 1997;77(2):359–396.
  • Pavlov TS, Levchenko V, Staruschenko A. Role of Rho GDP dissociation inhibitor α in control of epithelial sodium channel (ENaC)-mediated sodium reabsorption. J Biol Chem. 2014;289(41):28651–28659.
  • Karpushev AV, Levchenko V, Ilatovskaya DV, et al. Novel role of Rac1/WAVE signaling mechanism in regulation of the epithelial Na+ channel. Hypertension. 2011;57(5):996–1002.
  • Danser AH, Admiraal PJ, Derkx FH, et al. Angiotensin I-to-II conversion in the human renal vascular bed. J Hypertens. 1998;16(Supplement):2051–2056.
  • Van Kats JP, Schalekamp MA, Verdouw PD, et al. Intrarenal angiotensin II: interstitial and cellular levels and site of production. Kidney Int. 2001;60(6):2311–2317.
  • Seikaly MG, Arant Jr BS, Seney Jr FD. Endogenous angiotensin concentrations in specific intrarenal fluid compartments of the rat. J Clin Invest. 1990;86:1352–1357.
  • Hunyady L, Catt KJ. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol. 2006;20(5):953–970.
  • Balakumar P, Jagadeesh G. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology. Cell Signal. 2014;26(10):2147–2160.
  • Garrido AM, Griendling KK. NADPH oxidases and angiotensin II receptor signaling. Mol Cell Endocrinol. 2009;302(2):148–158.
  • Manickam N, Patel M, Griendling KK, et al. RhoA/Rho kinase mediates TGF-β1-induced kidney myofibroblast activation through Poldip2/Nox4-derived reactive oxygen species. Am J Physiol Renal Physiol. 2014;307(2):F159–71.
  • Hsu HH, Hoffmann S, Endlich N, et al. Mechanisms of angiotensin II signaling on cytoskeleton of podocytes. J Mol Med (Berl). 2008;86(12):1379–1394.
  • Macconi D, Abbate M, Morigi M, et al. Permselective dysfunction of podocyte-podocyte contact upon angiotensin II unravels the molecular target for renoprotective intervention. Am J Pathol. 2006;168(4):1073–1085.
  • López B, Salom MG, Arregui B, et al. Role of superoxide in modulating the renal effects of angiotensin II. Hypertension. 2003;42(6):1150–1156.
  • Nitschke R, Henger A, Ricken S, et al. Angiotensin II increases the intracellular calcium activity in podocytes of the intact glomerulus. Kidney Int. 2000;57(1):41–49.
  • Somlyo AP, Somlyo AV. Signal transduction by G-proteins, rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J Physiol. 2000;522:177–185.
  • Cavarape A, Bauer J, Bartoli E, et al. Effects of angiotensin II, arginine vasopressin and tromboxane A2 in renal vascular bed: role of rho-kinase. Nephrol Dial Transplant. 2003a;18(9):1764–1769.
  • Cavarape A, Endlich N, Assaloni R, et al. Rho-Kinase inhibition blunts renal vasoconstriction induced by distinct signaling pathways In Vivo. J Am Soc Nephrol. 2003b;14(1):37–45.
  • Ponnuchamy B, Khalil RA. Cellular mediators of renal vascular dysfunction in hypertension. Am J Physiol Regul Integr Comp Physiol. 2009;296(4):R1001–18.
  • Hoffmann S, Podlich D, Hähnel B, et al. Angiotensin II type 1 receptor overexpression in podocytes induces glomerulosclerosis in transgenic rats. J Am Soc Nephrol. 2004;15(6):1475–1487.
  • Carlström M, Wilcox CS, Arendshorst WJ. Renal autoregulation in health and disease. Physiol Rev. 2015;95:405–511.
  • Hodge RG, Ridley AJ. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol. 2016;17(8):496–510.
  • Fort P, Blangy A. The evolutionary landscape of Dbl-like RhoGEF families: adapting Eukaryotic cells to environmental signals. Genome Biol Evol. 2017;9(6):1471–1486.
  • Amin E, Jaiswal M, Derewenda U, et al. Deciphering the molecular and functional basis of RHOGAP family proteins: a systematic approach toward selective inactivation of Rho family proteins. J Biol Chem. 2016;291(39):20353–20371.
  • Garcia-Mata R, Boulter E, Burridge K. The ‘invisible hand’: regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol. 2011;12(8):493–504.
  • Narumiya S. The small GTPase Rho: cellular functions and signal transduction. J Biochem. 1996;120:215–228.
  • Ashraf S, Kudo H, Rao J, et al. Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment. Nat Commun. 2018;9(1):1960.
  • Braun DA, Lovric S, Schapiro D, et al. Mutations in multiple components of the nuclear pore complex cause nephrotic syndrome. J Clin Invest. 2018;128(10):4313–4328.
  • Ichinose K, Ushigusa T, Nishino A, et al. Lupus Nephritis IgG induction of Calcium/Calmodulin-dependent protein kinase IV expression in podocytes and alteration of their function. Arthritis Rheumatol. 2016;68(4):944–952.
  • Maeda K, Otomo K, Yoshida N, et al. CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease. J Clin Invest. 2018;128(8):3445–3459.
  • Hall G, Lane BM, Khan K, et al. The human FSGS-causing ANLN R431C mutation induces dysregulated PI3K/AKT/mTOR/Rac1 signaling in podocytes. J Am Soc Nephrol. 2018;29(8):2110–2122.
  • Eddy AA. Overview of the cellular and molecular basis of kidney fibrosis. Kidney Int Suppl. 2014;4(1):2–8.
  • Cao Q, Wang Y, Harris DC. Pathogenic and protective role of macrophages in kidney disease. Am J Physiol Renal Physiol. 2013;305(1):F3–11.
  • Nikolic-Paterson DJ, Atkins RC. The role of macrophages in glomerulonephritis. Nephrol Dial Transplant. 2001;16(5):3–7.
  • Wang Y, Harris DC. Macrophages in renal disease. J Am Soc Nephrol. 2011;22(1):21–27.
  • Matoba K, Kawanami D, Tsukamoto M, et al. Rho-kinase regulation of TNF-α-induced nuclear translocation of NF-κB RelA/p65 and M-CSF expression via p38 MAPK in mesangial cells. Am J Physiol Renal Physiol. 2014;307(5):F571–80.
  • Grande MT, Lopez-Novoa JM. Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol. 2009;5(6):319–328.
  • Strutz F, Zeisberg M. Renal fibroblasts and myofibroblasts in chronic kidney disease. J Am Soc Nephrol. 2006;17:2992–2998.
  • Bai S, Zeng R, Zhou Q, et al. Cdc42-interacting protein-4 promotes TGF-Β1-induced epithelial-mesenchymal transition and extracellular matrix deposition in renal proximal tubular epithelial cells. Int J Biol Sci. 2012;8(6):859–869.
  • Patel S, Takagi KI, Suzuki J, et al. RhoGTPase activation is a key step in renal epithelial mesenchymal transdifferentiation. J Am Soc Nephrol. 2005;16(7):1977–1984.
  • Gu L, Gao Q, Ni L, et al. Fasudil inhibits epithelial-myofibroblast transdifferentiation of human renal tubular epithelial HK-2 cells induced by high glucose. Chem Pharm Bull (Tokyo). 2013;61(7):688–694.
  • Wu G, Xu M, Xu K, et al. Benidipine protects kidney through inhibiting ROCK1 activity and reducing the epithelium-mesenchymal transdifferentiation in type 1 diabetic rats. J Diabetes Res. 2013;2013:174526.
  • Guzzi F, Cirillo L, Roperto RM, et al. Molecular mechanisms of the acute kidney injury to chronic kidney disease transition: an updated view. Int J Mol Sci. 2019;20(19):4941.
  • Zhang WR, Parikh CR. Biomarkers of acute and chronic kidney disease. Annu Rev Physiol. 2019;81(1):309–333.
  • Humphreys BD, Czerniak S, DiRocco DP, et al. Repair of injured proximal tubule does not involve specialized progenitors. Proc Natl Acad Sci USA. 2011;108(22):9226–9231.
  • Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.
  • Patel S, Tang J, Overstreet JM, et al. Rac-GTPase promotes fibrotic TGF-β1 signaling and chronic kidney disease via EGFR, p53, and Hippo/YAP/TAZ pathways. Faseb J. 2019;33(9):9797–9810.
  • Lin JS, Susztak K. Podocytes: the weakest link in diabetic kidney disease? Curr Diab Rep. 2016;16(5):45.
  • Kawanami D, Matoba K, Utsunomiya K. Signaling pathways in diabetic nephropathy. Histol Histopathol. 2016;31(10):1059–1067.
  • Komers R. Rho kinase inhibition in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2011;20(1):77–83.
  • Komers R. Rho kinase inhibition in diabetic kidney disease. Br J Clin Pharmacol. 2013;76(4):551–559.
  • Massey AR, Miao L, Smith BN, et al. Increased RhoA translocation in renal cortex of diabetic rats. Life Sci. 2003;72(26):2943–2952.
  • Danesh FR, Sadeghi MM, Amro N, et al. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy. Proc Natl Acad Sci USA. 2002;99(12):8301–8305.
  • Kolavennu V, Zeng L, Peng H, et al. Targeting of RhoA/ROCK signaling ameliorates progression of diabetic nephropathy independent of glucose control. Diabetes. 2008;57(3):714–723.
  • Peng F, Wu D, Gao B, et al. RhoA/Rho-kinase contribute to the pathogenesis of diabetic renal disease. Diabetes. 2008;57(6):1683–1692.
  • Nagai Y, Matoba K, Kawanami D, et al. ROCK2 regulates TGF-β-induced expression of CTGF and profibrotic genes via NF-κB and cytoskeleton dynamics in mesangial cells. Am J Physiol Renal Physiol. 2019;317(4):F839–51.
  • Sharma D, Gondaliya P, Tiwari V, et al. Kaempferol attenuates diabetic nephropathy by inhibiting RhoA/Rho-kinase mediated inflammatory signalling. Biomed Pharmacother. 2019;109:1610–1619.
  • Pourshabanan P, Momeni A, Mahmoudnia L, et al. Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy. Diabetes Metab Syndr. 2019;13(1):132‐6.
  • Wakino S, Hayashi K, Kanda T, et al. Peroxisome proliferator-activated receptor gamma ligands inhibit Rho/Rho kinase pathway by inducing protein tyrosine phosphatase SHP-2. Circ Res. 2004;95(5):e45‐e55.
  • Grieshammer U, Le M, Plump AS, et al. SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev Cell. 2004;6(5):709–717.
  • Pan Y, Jiang S, Hou Q, et al. Dissection of glomerular transcriptional profile in patients with diabetic nephropathy: SRGAP2a protects podocyte structure and function. Diabetes. 2018;67(4):717–730.
  • Wang S, Chen C, Su K, et al. Angiotensin II induces reorganization of the actin cytoskeleton and myosin light-chain phosphorylation in podocytes through rho/ROCK-signaling pathway. Ren Fail. 2016;38(2):268–275.
  • Komers R, Plotkin H. Dual inhibition of renin-angiotensin-aldosterone system and endothelin-1 in treatment of chronic kidney disease. Am J Physiol Regul Integr Comp Physiol. 2016;310(10):R877–84.
  • Yacoub R, Campbell KN. Inhibition of RAS in diabetic nephropathy. Int J Nephrol Renovasc Dis. 2015;8:29–40.
  • Xie X, Peng J, Chang X, et al. Liu P and Huang H: activation of RhoA/ROCK regulates NF-κB signaling pathway in experimental diabetic nephropathy. Mol Cell Endocrinol. 2013;369(1–2):86–97.
  • Huang Z, Peng Y, Yu H, et al. RhoA protects the podocytes against high glucose-induced apoptosis through YAP and plays critical role in diabetic nephropathy. Biochem Biophys Res Commun. 2018;504(4):949–956.
  • Zhou L, Liu F, Huang XR, et al. Amelioration of albuminuria in ROCK1 knockout mice with streptozotocin-induced diabetic kidney disease. Am J Nephrol. 2011;34(5):468–475.
  • Gojo A, Utsunomiya K, Taniguchi K, et al. The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats. Eur J Pharmacol. 2007;568(1–3):242–247.
  • Kikuchi Y, Yamada M, Imakiire T, et al. A Rho-kinase inhibitor, fasudil, prevents development of diabetes and nephropathy in insulin-resistant diabetic rats. J Endocrinol. 2007;192(3):595–603.
  • Matoba K, Kawanami D, Okada R, et al. Rho-kinase inhibition prevents the progression of diabetic nephropathy by downregulating hypoxia-inducible factor 1α. Kidney Int. 2013;84(3):545–554.
  • Matoba K, Kawanami D, Nagai Y, et al. Rho-Kinase blockade attenuates podocyte apoptosis by inhibiting the notch signaling pathway in diabetic nephropathy. Int J Mol Sci. 2017;18:10.3390.
  • Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci U S A. 2006;103(8):2653–2658.
  • Wang W, Wang Y, Long J, et al. Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells. Cell Metab. 2012;15(2):186–200.
  • Huang QY, Lai XN, Qian XL, et al. Cdc42: a novel regulator of insulin secretion and diabetes-associated diseases. Int J Mol Sci. 2019;20(1):179.
  • Fernández D, Horrillo A, Alquezar C, et al. Control of cell adhesion and migration by podocalyxin. Implication of Rac1 and Cdc42. Biochem Biophys Res Commun. 2013;432(2):302–307.
  • Ichii O, Otsuka-Kanazawa S, Nakamura T, et al. Podocyte injury caused by indoxyl sulfate, a uremic toxin and aryl-hydrocarbon receptor ligand. PLoS ONE. 2014;9(9):e108448.
  • Shen J, Wang R, He Z, et al. NMDA receptors participate in the progression of diabetic kidney disease by decreasing Cdc42-GTP activation in podocytes. J Pathol. 2016;240:149–160.
  • Gao SY, Li CY, Shimokawa T, et al. Rho-family small GTPases are involved in forskolin-induced cell-cell contact formation of renal glomerular podocytes in vitro. Cell Tissue Res. 2007;328(2):391–400.
  • Lin J, Shi Y, Peng H, et al. Loss of PTEN promotes podocyte cytoskeletal rearrangement, aggravating diabetic nephropathy. J Pathol. 2015;236(1):30–40.
  • Kim SH, Jang YW, Hwang P, et al. The reno-protective effect of a phosphoinositide 3-kinase inhibitor wortmannin on streptozotocin-induced proteinuric renal disease rats. Exp Mol Med. 2012;44(1):45–51.
  • Zhu J, Sun N, Aoudjit L, et al. Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int. 2008;73(5):556–566.
  • Lin CL, Wang JY, Ko JY, et al. Superoxide destabilization of beta-catenin augments apoptosis of high-glucose-stressed mesangial cells. Endocrinology. 2008;149(6):2934–2942.
  • Gumustekin M, Micili SC, Arici MA, et al. The effect of insulin treatment on Rac1 expression in diabetic kidney. Ren Fail. 2013;35(3):396–402.
  • Ishizaka M, Gohda T, Takagi M, et al. Podocyte-specific deletion of Rac1 leads to aggravation of renal injury in STZ-induced diabetic mice. Biochem Biophys Res Commun. 2015;467(3):549–555.
  • Lv Z, Hu M, Fan M, et al. Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice. Cell Death Dis. 2018;9(3):342.
  • Yoshida S, Ishizawa K, Ayuzawa N, et al. Local mineralocorticoid receptor activation and the role of Rac1 in obesity-related diabetic kidney disease. Nephron Exp Nephrol. 2014;126(1):16–24.
  • Grove KJ, Voziyan PA, Spraggins JM, et al. Diabetic nephropathy induces alterations in the glomerular and tubule lipid profiles. J Lipid Res. 2014;55(7):1375–1385.
  • Kim D, Li HY, Lee JH, et al. Lysophosphatidic acid increases mesangial cell proliferation in models of diabetic nephropathy via Rac1/MAPK/KLF5 signaling. Exp Mol Med. 2019;51:1–10.
  • Loirand G, Pacaud P. Involvement of Rho GTPases and their regulators in the pathogenesis of hypertension. Small GTPases. 2014;5(4):1–10.
  • Guan Z, Baty JJ, Zhang S, et al. Rho kinase inhibitors reduce voltage-dependent Ca2+ channel signaling in aortic and renal microvascular smooth muscle cells. Am J Physiol Renal Physiol. 2019;317(5):F1132–41.
  • Nagase M, Fujita T. Role of Rac1-mineralocorticoid-receptor signalling in renal and cardiac disease. Nat Rev Nephrol. 2013;9(2):86–98.
  • Shibata S, Nagase M, Yoshida S, et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: implication in proteinuric kidney disease. Nat Med. 2008;14:1370–1376.
  • Hayashi H, Szászi K, Coady-Osberg N, et al. Inhibition and redistribution of NHE3, the apical Na+/H+ exchanger, by Clostridium difficile toxin B. J Gen Physiol. 2004;123(5):491–504.
  • Nishiki K, Tsuruoka S, Kawaguchi A, et al. Inhibition of Rho-kinase reduces renal Na-H exchanger activity and causes natriuresis in rat. J Pharmacol Exp Ther. 2003;304(2):723–728.
  • Shibata S, Mu S, Kawarazaki H, et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J Clin Invest. 2011;121:3233–3243.
  • Robins R, Baldwin C, Aoudjit L, et al. Loss of Rho-GDIα sensitizes podocytes to lipopolysaccharide-mediated injury. Am J Physiol Renal Physiol. 2015;308:F1207–16.
  • McCaffrey JC, Webb NJ, Poolman TM, et al. Glucocorticoid therapy regulates podocyte motility by inhibition of Rac1. Sci Rep. 2017;7(1):6725.
  • Maier M, Baldwin C, Aoudjit L, et al. The role of Trio, a Rho Guanine nucleotide exchange factor, in glomerular podocytes. Int J Mol Sci. 2018;19(2):479.
  • Brähler S, Yu H, Suleiman H, et al. Intravital and kidney slice imaging of podocyte membrane dynamics. J Am Soc Nephrol. 2016;27(11):3285–3290.
  • Togawa A, Miyoshi J, Ishizaki H, et al. Progressive impairment of kidneys and reproductive organs in mice lacking Rho GDIα. Oncogene. 1999;18(39):5373–5380.
  • Akilesh S, Suleiman H, Yu H, et al. Arhgap24 inactivates Rac1 in mouse podocytes, and a mutant form is associated with familial focal segmental glomerulosclerosis. J Clin Invest. 2011;121(10):4127–4137.
  • Gee HY, Saisawat P, Ashraf S, et al. ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling. J Clin Invest. 2013;123(8):3243–3253.
  • Gupta IR, Baldwin C, Auguste D, et al. ARHGDIA: a novel gene implicated in nephrotic syndrome. J Med Genet. 2013;50(5):330–338.
  • Auguste D, Maier M, Baldwin C, et al. Disease-causing mutations of RhoGDIα induce Rac1 hyperactivation in podocytes. Small GTPases. 2016;7(2):107–121.
  • Schaldecker T, Kim S, Tarabanis C, et al. Inhibition of the TRPC5 ion channel protects the kidney filter. J Clin Invest. 2013;123(12):5298–5309.
  • Sun Y, Guo C, Ma P, et al. Kindlin-2 association with Rho GDP-dissociation inhibitor α suppresses Rac1 activation and podocyte injury. J Am Soc Nephrol. 2017;28:3545–3562.
  • Yasuda-Yamahara M, Rogg M, Frimmel J, et al. FERMT2 links cortical actin structures, plasma membrane tension and focal adhesion function to stabilize podocyte morphology. Matrix Biol. 2018;68–69:263–279.
  • Hatano R, Takeda A, Abe Y, et al. Loss of ezrin expression reduced the susceptibility to the glomerular injury in mice. Sci Rep. 2018;8(1):4512.
  • Wilson PD. Polycystic kidney disease: new understanding in the pathogenesis. Int J Biochem Cell Biol. 2004;36(10):1868–1873.
  • Cai J, Song X, Wang W, et al. A RhoA–YAP–c-Myc signaling axis promotes the development of polycystic kidney disease. Genes Dev. 2018;32(11–12):781–793.
  • Zallocchi M, Johnson BM, Meehan DT, et al. α1β1 integrin/Rac1-dependent mesangial invasion of glomerular capillaries in Alport syndrome. Am J Pathol. 2013;183(4):1269–1280.
  • Lu TC, He JC, Wang ZH, et al. HIV-1 Nef disrupts the podocyte actin cytoskeleton by interacting with diaphanous interacting protein. J Biol Chem. 2008;283:8173–8182.
  • Tan R, Patni H, Tandon P, et al. Nef interaction with actin compromises human podocyte actin cytoskeletal integrity. Exp Mol Pathol. 2013;94(1):51–57.
  • Xie X, Colberg-Poley AM, Das JR, et al. The basic domain of HIV-tat transactivating protein is essential for its targeting to lipid rafts and regulating fibroblast growth factor-2 signaling in podocytes isolated from children with HIV-1-associated nephropathy. J Am Soc Nephrol. 2014;25(8):1800–1813.
  • Tokuyama H, Wakino S, Hara Y, et al. Role of mineralocorticoid receptor/Rho/Rho-kinase pathway in obesity-related renal injury. Int J Obes (Lond). 2012;36(8):1062–1071.
  • Pojoga LH, Baudrand R, Adler GK. Mineralocorticoid receptor throughout the vessel: a key to vascular dysfunction in obesity. Eur Heart J. 2013;34:3475–3477.
  • Wang YD, Zhang L, Cai GY, et al. Fasudil ameliorates rhabdomyolysis-induced acute kidney injury via inhibition of apoptosis. Ren Fail. 2011;33(8):811–818.
  • Fu P, Liu F, Su S, et al. Signaling mechanism of renal fibrosis in unilateral ureteral obstructive kidney disease in ROCK1 knockout mice. J Am Soc Nephrol. 2006;17(11):3105–3114.
  • Calizo RC, Bhattacharya S, Van Hasselt JGC, et al. Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity. Nat Commun. 2019;10(1):2061.
  • Becker MS, Müller PM, Bajorat J, et al. The anticancer phytochemical rocaglamide inhibits Rho GTPase activity and cancer cell migration. Oncotarget. 2016;7(32):51908–51921.
  • Pernis AB, Ricker E, Weng CH, et al. Rho kinases in autoimmune diseases. Annu Rev Med. 2016;67(1):355–374.
  • Biswas PS, Gupta S, Chang E, et al. Phosphorylation of IRF4 by ROCK2 regulates IL-17 and IL-21 production and the development of autoimmunity in mice. J Clin Invest. 2010;120(9):3280–3295.
  • Rozo C, Chinenov Y, Maharaj RK, et al. Targeting the RhoA-ROCK pathway to reverse T-cell dysfunction in SLE. Ann Rheum Dis. 2017;76(4):740–747.
  • Li Y, Harada T, Juang YT, et al. Phosphorylated ERM is responsible for increased T cell polarization, adhesion, and migration in patients with systemic lupus erythematosus. J Immunol. 2007;178(3):1938–1947.
  • Stirzaker R, Biswas P, Gupta S, et al. Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus. 2012;21(6):656–661.
  • Isgro J, Gupta S, Jacek E, et al. Enhanced rho-associated protein kinase activation in patients with systemic lupus erythematosus. Arthritis Rheum. 2013;65(6):1592–1602.
  • Fried LF. Effects of HMG-CoA reductase inhibitors (statins) on progression of kidney disease. Kidney Int. 2008;74(5):571–576.
  • Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21(11):1712–1719.
  • Bruder-Nascimento T, Callera G, Montezano AC, et al. Renoprotective effects of atorvastatin in diabetic mice: downregulation of RhoA and upregulation of Akt/GSK3. PLoS One. 2016;11(9):e0162731.
  • Li W, Zhang Y, Bouley R, et al. Simvastatin enhances aquaporin-2 surface expression and urinary concentration in vasopressin-deficient Brattleboro rats through modulation of Rho GTPase. Am J Physiol Renal Physiol. 2011;301(2):F309–18.
  • Thompson JM, Alvarez A, Singha MK, et al. Targeting the mevalonate pathway suppresses VHL-deficient CC-RCC through an HIF-dependent mechanism. Mol Cancer Ther. 2018;17:1781–1792.
  • Ohigashi M, Kobara M, Takahashi T, et al. Pitavastatin suppresses hyperglycaemia-induced podocyte injury via bone morphogenetic protein-7 preservation. Clin Exp Pharmacol Physiol. 2017;44(3):378–385.
  • Rysz J, Franczyk B, Radek M, et al. Diabetes and cardiovascular risk in renal transplant patients. Int J Mol Sci. 2021;22:3422.
  • Premasathian NC, Muehrer R, Brazy PC, et al. Blood pressure control in kidney transplantation: therapeutic implications. J Hum Hypertens. 2004;18:871–877.
  • Calò LA, Ravarotto V, Simioni F, et al. Pathophysiology of post transplant hypertension in kidney transplant: focus on calcineurin inhibitors induced oxidative stress and renal sodium retention and implications with RhoA/Rho kinase pathway. Kidney Blood Press Res. 2017;42(4):676–685.
  • Büssemaker E, Herbrig K, Pistrosch F, et al. Role of rho-kinase in the regulation of vascular tone in hypertensive renal transplant recipients. Atherosclerosis. 2009;207(2):567–572.
  • Martin-Martin N, Dan Q, Amoozadeh Y, et al. RhoA and Rho kinase mediate cyclosporine A and sirolimus-induced barrier tightening in renal proximal tubular cells. Int J Biochem Cell Biol. 2012;44(1):178–188.
  • Takemoto M, Sun J, Hiroki J, et al. Rhokinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase. Circulation. 2002;106(1):57–62.
  • Caron A, Desrosiers RR, Béliveau R. Kidney ischemia–reperfusion regulates expression and distribution of tubulin subunits, β-actin and rho GTPases in proximal tubules. Arch Biochem Biophys. 2004;431(1):31–46.
  • Gao G, Wang W, Tadagavadi RK, et al. TRPM2 mediates ischemic kidney injury and oxidant stress through RAC1. J Clin Invest. 2014;124(11):4989–5001.
  • Barrera-Chimal J, André-Grégoire G, Nguyen Dinh Cat A, et al. Benefit of mineralocorticoid receptor antagonism in AKI: role of vascular smooth muscle Rac1. J Am Soc Nephrol. 2017;28(4):1216–1226.
  • Liang H, Huang J, Huang Q, et al. Pharmacological inhibition of Rac1 exerts a protective role in ischemia/reperfusion-induced renal fibrosis. Biochem Biophys Res Commun. 2018;503(4):2517–2523.
  • Poosti F, Yazdani S, Dolman ME, et al. Targeted inhibition of renal Rho kinase reduces macrophage infiltration and lymphangiogenesis in acute renal allograft rejection. Eur J Pharmacol. 2012;694(1–3):111–119.
  • Prakash J, De Borst MH, Lacombe M, et al. Inhibition of renal Rho kinase attenuates Ischemia/Reperfusion-induced injury. J Am Soc Nephrol. 2008;19(11):2086–2097.
  • Dallery-Prudhomme E, Roumier C, Denis C, et al. Genomic structure and assignment of the RhoH/TTF small GTPase gene (ARHH) to 4p13 by in situ hybridization. Genomics. 1997;43(1):89–94.
  • Li X, Bu X, Lu B, et al. The hematopoiesis-specific GTP-binding protein RhoH is GTPase deficient and modulates activities of other Rho GTPases by an inhibitory function. Mol Cell Biol. 2002;22(4):1158–1171.
  • Porubsky S, Wang S, Kiss E, et al. Rhoh deficiency reduces peripheral T-cell function and attenuates allogenic transplant rejection. Eur J Immunol. 2011;41(1):76–88.
  • Dorn T, Kuhn U, Bungartz G, et al. RhoH is important for positive thymocyte selection and T‐cell receptor signaling. Blood. 2007;109(6):2346–2355.
  • Kezić A, Stajic N, Thaiss F. Innate immune response in kidney Ischemia/Reperfusion injury: potential target for therapy. J Immunol Res. 2017;2017:6305439.
  • Nakamura K, Kageyama S, Kupiec-Weglinski JW. Innate immunity in ischemia-reperfusion injury and graft rejection. Curr Opin Organ Transplant. 2019;24:687–693.
  • Bros M, Haas K, Moll L, et al. RhoA as a Key regulator of innate and adaptive immunity. Cells. 2019;8(7):733.
  • Li L, Huang L, Sung SS, et al. NKT cell activation mediates neutrophil IFN-γ production and renal ischemia-reperfusion injury. J Immunol. 2007;178(9):5899–5911.
  • Basbous S, Levescot A, Piccirilli N, et al. The Rho-ROCK pathway as a new pathological mechanism of innate immune subversion in chronic myeloid leukaemia. J Pathol. 2016;240(3):262–268.
  • Sánchez-Madrid F, Del Pozo MA. Leukocyte polarization in cell migration and immune interactions. EMBO J. 1999;18(3):501–511.
  • García-Ortiz A, Serrador JM. ERM proteins at the crossroad of Leukocyte polarization, migration and intercellular adhesion. Int J Mol Sci. 2020;21(4):1502.
  • Kamburova EG, Gruijters ML, Kardol-Hoefnagel T, et al. Antibodies against ARHGDIB are associated with long-term kidney graft loss. Am J Transplant. 2019;19(12):3335–3344.
  • Senev A, Otten HG, Kamburova EG, et al. Antibodies against ARHGDIB and ARHGDIB gene expression associate with kidney allograft outcome. Transplantation. 2020;104(7):1462–1471.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.