Increased RhoA translocation in renal cortex of diabetic rats

Massey, Amber R; Miao, Li’yang; Smith, Brandi N; Liu, Jiankang; Kusaka, Ikuyo; Zhang, Junyi; Tang, Jiping

doi:10.1016/s0024-3205(03)00228-5

Cited by 28 publications

(17 citation statements)

References 26 publications

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“…This response was characterized by renal vasodilation, indicated by increases in ERPF, reductions in RVR and a decrease in FF. The enhanced renal response to ROCK inhibitors was in agreement with accumulating evidence indicating activation of RhoA/ROCK in the diabetic kidney in vitro and in vivo (Massey et al, 2003;Banes-Berceli et al, 2006;Kolavennu et al, 2008;Peng et al, 2008), and indicated greater dependence of renal haemodynamics on RhoA/ROCK in diabetes.…”

Section: Figuresupporting

confidence: 87%

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

Komers

Oyama

Beard

et al. 2010

British J Pharmacology

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BACKGROUND AND PURPOSE The RhoA/Rho associated kinases (ROCK) pathway has been implicated in the pathophysiology of diabetic nephropathy (DN). Early stages of diabetes are associated with renal haemodynamic changes, contributing to later development of DN. However, the role of RhoA/ROCK, known regulators of vascular tone, in this process has not been studied.EXPERIMENTAL APPROACH Blood pressure (BP), glomerular filtration (GFR), effective renal plasma flow and filtration fraction (FF) in response to the ROCK inhibitors Y27632 (0.1 and 0.5 mg·kg−1) and fasudil (0.3 and 1.5 mg·kg−1) were examined in streptozotocin‐diabetic rats and non‐diabetic controls.KEY RESULTS Diabetic rats demonstrated baseline increases in GFR and FF. In contrast to similar decreases in BP in diabetic and control rats, renal vasodilator effects and a decrease in FF, following ROCK inhibition were observed only in diabetic rats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabetic rats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabetic rats were modulated by prior protein kinase C (PKC)β inhibition with ruboxistaurin, which abolished their effects on FF. Consistent with the renal vasodilator effects, the ROCK inhibitors reduced phosphorylation of myosin light chain in diabetic kidneys.CONCLUSIONS AND IMPLICATIONS The results indicate greater dependence of renal haemodynamics on RhoA/ROCK and beneficial haemodynamic effects of ROCK inhibitors in diabetes, which were additive to the effects of losartan. In this process, the RhoA/ROCK pathway operated downstream of or interacted with, PKCβ in some segments of the renal vascular tree.

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Section: Figuresupporting

confidence: 87%

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

Komers

Oyama

Beard

et al. 2010

British J Pharmacology

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“…Recent studies have shown changes in RhoA activation in diabetes. In streptozotocin (STZ)-treated diabetic rats, an increase in membranebound RhoA was seen in the renal cortex (8,9). Similar observations, preceding overt pathologic changes, were made in the basilar artery and aorta (10,11).…”

supporting

confidence: 60%

RhoA/Rho-Kinase Contribute to the Pathogenesis of Diabetic Renal Disease

et al. 2008

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OBJECTIVE—Accumulation of glomerular matrix proteins is central to the pathogenesis of diabetic nephropathy, with resident mesangial cells (MCs) known to upregulate matrix protein synthesis in response to high glucose. Because activation of the GTPase RhoA has been implicated in matrix upregulation, we studied its role in induction of the matrix protein fibronectin in diabetic MCs and in vivo in diabetic nephropathy. RESEARCH DESIGN AND METHODS—Glucose (30 mmol/l)-induced RhoA/Rho-kinase, AP-1 activation, and fibronectin upregulation were assessed by immunoblotting, luciferase, electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, real-time PCR, Northern blots, and immunofluorescence. Streptozotocin-induced diabetic rats were treated with the ρ-kinase inhibitor fasudil, which was compared with enalapril, and functional and pathologic parameters were assessed. RESULTS—Glucose led to RhoA and downstream Rho-kinase activation. Mannitol was without effect. Activity of the transcription factor AP-1, increased in diabetic MCs and kidneys, is important in the profibrotic effects of glucose, and this was dependent on Rho-kinase signaling. Upregulation of fibronectin by glucose, shown to be mediated by activator protein-1 (AP-1), was prevented by Rho-kinase inhibition. RhoA siRNA and dominant-negative RhoA also markedly attenuated fibronectin upregulation by high glucose. Applicability of these findings were tested in vivo. Fasudil prevented glomerular fibronectin upregulation, glomerular sclerosis, and proteinuria in diabetic rats, with effectiveness similar to enalapril. CONCLUSIONS—High glucose activates RhoA/Rho-kinase in MCs, leading to downstream AP-1 activation and fibronectin induction. Inhibition of this pathway in vivo prevents the pathologic changes of diabetic nephropathy, supporting a potential role for inhibitors of RhoA/Rho in the treatment of diabetic renal disease.

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“…Rho A and ROCK Are Activated by HG in HK-2 Cells Since increased RhoA activation has been observed in the renal cortex and mesangial cells of diabetic animals exposed to high glucose, 25,26) we investigated whether high glucose would activate RhoA in HK-2 cells, using a pull-down assay. /Thr 696 ) levels were measured using a co-immunoprecipitation assay, after HK-2 cells were exposed to HG for 0, 0.5, 1, 3, 7, 12 and 24 h. ROCK activity is expressed as the ratio of phospho-MYPT 1 (Thr 853 or Thr 696 ) to ROCK.…”

Section: Resultsmentioning

confidence: 99%

“…ROCK was the first identified RhoA effector, and is the best characterized. A recent study suggested that RhoA is activated in the renal cortex of diabetic rats, 25) and that high glucose levels activate RhoA in renal mesangial cells. 26) Most in vitro studies of high glucose-induced RhoA/ROCK activation in the kidney focused on glomerular mesangial cells.…”

mentioning

confidence: 99%

Fasudil Inhibits Epithelial-Myofibroblast Transdifferentiation of Human Renal Tubular Epithelial HK-2 Cells Induced by High Glucose

Gao

et al. 2013

CHEMICAL & PHARMACEUTICAL BULLETIN

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Renal fibrosis is a crucial pathologic process underlying diabetic nephropathy (DN). Central to this process is the epithelial-mesenchymal transformation (EMT) of tubular epithelial cells. Fasudil, a Rho-associated coiled-coil forming protein serine/threonine kimase (ROCK) inhibitor, protects against renal fibrosis in a variety of renal injury models. However, fasudil's effects on renal fibrosis in DN remain unknown. The aim of the present study was to investigate the effects of fasudil on high glucose-induced EMT in human renal tubular epithelial (HK-2) cells. HK-2 cells were exposed to 5.5 or 60 mmol/L d-glucose for 72h, or to mannitol (osmotic control). RhoA activity was assessed using a RhoA pull-down assay, and ROCK activity was determined by myosin phosphatase target subunit-1 (

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Increased RhoA translocation in renal cortex of diabetic rats

Cited by 28 publications

References 26 publications

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

Effects of systemic inhibition of Rho kinase on blood pressure and renal haemodynamics in diabetic rats

RhoA/Rho-Kinase Contribute to the Pathogenesis of Diabetic Renal Disease

Fasudil Inhibits Epithelial-Myofibroblast Transdifferentiation of Human Renal Tubular Epithelial HK-2 Cells Induced by High Glucose

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