Activin A and Cell-Surface GRP78 Are Novel Targetable RhoA Activators for Diabetic Kidney Disease.
Diabetic kidney disease (DKD) is the leading cause of kidney failure. RhoA/Rho-associated protein kinase (ROCK) signaling is a recognized mediator of its pathogenesis, largely through mediating the profibrotic response. While RhoA activation is not feasible due to the central role it plays in normal physiology, ROCK inhibition has been found to be effective in attenuating DKD in preclinical models. However, this has not been evaluated in clinical studies as of yet. Alternate means of inhibiting RhoA/ROCK signaling involve the identification of disease-specific activators. This report presents evidence showing the activation of RhoA/ROCK signaling both in vitro in glomerular mesangial cells and in vivo in diabetic kidneys by two recently described novel pathogenic mediators of fibrosis in DKD, activins and cell-surface GRP78. Neither are present in normal kidneys. Activin inhibition with follistatin and neutralization of cell-surface GRP78 using a specific antibody blocked RhoA activation in mesangial cells and in diabetic kidneys. These data identify two novel RhoA/ROCK activators in diabetic kidneys that can be evaluated for their efficacy in inhibiting the progression of DKD.
['Soomro|Asfia|A|', 'Trink|Jackie|J|', "O'Neil|Kian|K|", 'Li|Renzhong|R|', 'Naiel|Safaa|S|', 'Gao|Bo|B|', 'Ask|Kjetil|K|', 'Krepinsky|Joan C|JC|0000-0002-6761-909X']
D028341:Activins D000818:Animals D057134:Antibodies, Neutralizing D003921:Diabetes Mellitus, Experimental D003928:Diabetic Nephropathies D004195:Disease Models, Animal D000091342:Endoplasmic Reticulum Chaperone BiP D038681:Follistatin D005786:Gene Expression Regulation D006360:Heat-Shock Proteins D006801:Humans D008297:Male D050527:Mesangial Cells D051379:Mice D008810:Mice, Inbred C57BL D009392:Nephrectomy D061251:Primary Cell Culture D015398:Signal Transduction D013311:Streptozocin D054460:rho-Associated Kinases D020742:rhoA GTP-Binding Protein
activins cell-surface GRP78 RhoA diabetic kidney disease fibrosis Rho-kinase