Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

Cavarape, Alessandro; Endlich, Nicole; Assaloni, Roberta; Bartoli, Ettore; Steinhausen, M.; Parekh, N.; Endlich, Karlhans

doi:10.1097/01.asn.0000039568.93355.85

Cited by 64 publications

(67 citation statements)

References 55 publications

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“…Studies using local administration of inhibitors in intact rats have reported ROCK inhibitor-induced dose-dependent increases renal blood flow (Bauer and Parekh, 2003;Cavarape et al, 2003b). At the glomerular level, measurements utilizing videomicroscopy in isolated split rat hydronephrotic kidneys or the in vitro blood-perfused juxtamedullary nephron technique have determined that ROCK inhibitors induce predominantly afferent and lesser efferent, arteriolar dilation (Cavarape et al, 2003b;Nakamura et al, 2003;Inscho et al, 2009). In the present studies, the whole kidney haemodynamic pattern induced by ROCK inhibitors in diabetic rats suggests not only afferent but also an important efferent effect of these compounds in diabetic rats.…”

Section: Figurementioning

confidence: 99%

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: Figurementioning

confidence: 99%

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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“…, a concentration at least twice the maximal stimulatory concentrations reported in the literature (Just et al, 2004;Touyz et al, 1995;Shimoda et al, 2000;Yanagisawa et al, 1988;Cavarape et al, 2003;Batra et al, 1993). The concentrations of antagonists were also chosen on the basis of values reported in the literature: Zn 2+ (3·mmol·l -1 ) (de Toledo et al, 2000), nicotinamide (3·mmol·l -1 ) (Sethi et al, 1996), 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (TEMPOL; 1·mmol·l -1 ) (Zhang et al, 2004;Touyz et al, 2004) and diphenyl iodonium (DPI; 1·µmol·l -1 ) (Touyz et al, 2004;Rodriguez-Puyol et al, 2002).…”

Section: Experimental Protocolmentioning

confidence: 76%

Endothelin-1, superoxide and adeninediphosphate ribose cyclase in shark vascular smooth muscle

Fellner

Parker

2005

Journal of Experimental Biology

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“…Thus, recent studies demonstrate that Rhokinase inhibition by Y-27632 and fasudil dilates basal tone of afferent as well as efferent arterioles in the in vitro (10) and in vivo hydronephrotic kidney models (11), although the vasodilator response of efferent arterioles is slightly less than that of afferent arterioles. Furthermore, both Y-27632 and fasudil reverse the angiotensin II-induced vasoconstriction of afferent and efferent arterioles (Fig.…”

Section: Role Of Rho / Rho-kinase In the Kidneymentioning

confidence: 97%

Molecular Mechanisms and Therapeutic Strategies of Chronic Renal Injury: Role of Rho-Kinase in the Development of Renal Injury

et al. 2006

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Abstract. Rho/ Rho-kinase plays an important role not only in the vasoconstrictor mechanism but also in cellular morphology, motility, adhesion, and proliferation. This pathway also serves to modulate the structure and function of various kidney cells including tubular epithelial cells, mesangial cells, and podocytes. The inhibition of the Rho / Rho-kinase pathway elicits marked increases in renal blood flow in vivo and dilates both afferent and efferent arterioles preconstricted by angiotensin II in vitro. In renal injury, intrarenal angiotensin II is reported to be activated, which subsequently would upregulate the Rho-kinase pathway. A selective Rho-kinase inhibitor, fasudil, has recently been shown to improve renal damage resulting from hypertensive glomerulosclerosis, unilateral ureteral obstruction (for interstitial renal fibrosis) and subtotal nephrectomy. Of interest, fasudil upregulated the expression of p27 kip1 , a cyclin-dependent kinase inhibitor, and increased the p27 kip1 immuno-positive cells in both glomeruli and tubulointerstitium with the use of immunohistochemistry. Collectively, the Rho-kinase pathway is involved in the pathogenesis of renal injury. Clinical application of this type of therapy however awaits further investigations.

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Rho-Kinase Inhibition Blunts Renal Vasoconstriction Induced by Distinct Signaling Pathways In Vivo

Cited by 64 publications

References 55 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

Endothelin-1, superoxide and adeninediphosphate ribose cyclase in shark vascular smooth muscle

Molecular Mechanisms and Therapeutic Strategies of Chronic Renal Injury: Role of Rho-Kinase in the Development of Renal Injury

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