Abstract
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.
Keywords:
Rho-kinase; RhoA; activins; cell-surface GRP78; diabetic kidney disease; fibrosis.
MeSH terms
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Activins / antagonists & inhibitors
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Activins / genetics*
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Activins / metabolism
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Animals
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Antibodies, Neutralizing / pharmacology
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Diabetes Mellitus, Experimental / chemically induced
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Diabetes Mellitus, Experimental / drug therapy
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Diabetes Mellitus, Experimental / genetics*
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Diabetes Mellitus, Experimental / metabolism
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Diabetic Nephropathies / drug therapy
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Diabetic Nephropathies / genetics
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Diabetic Nephropathies / metabolism
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Diabetic Nephropathies / pathology
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Disease Models, Animal
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Endoplasmic Reticulum Chaperone BiP
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Follistatin / pharmacology
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Gene Expression Regulation
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Heat-Shock Proteins / antagonists & inhibitors
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Heat-Shock Proteins / genetics*
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Heat-Shock Proteins / metabolism
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Humans
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Male
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Mesangial Cells / drug effects
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Mesangial Cells / metabolism*
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Mesangial Cells / pathology
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Mice
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Mice, Inbred C57BL
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Nephrectomy / methods
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Primary Cell Culture
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Signal Transduction
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Streptozocin / administration & dosage
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rho-Associated Kinases / genetics
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rho-Associated Kinases / metabolism
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rhoA GTP-Binding Protein / genetics*
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rhoA GTP-Binding Protein / metabolism
Substances
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Antibodies, Neutralizing
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Endoplasmic Reticulum Chaperone BiP
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Follistatin
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HSPA5 protein, human
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Heat-Shock Proteins
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Hspa5 protein, mouse
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activin A
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Activins
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Streptozocin
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Rock1 protein, mouse
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Rock2 protein, mouse
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rho-Associated Kinases
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RhoA protein, mouse
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rhoA GTP-Binding Protein