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

Abstract

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.

Myosin Light Chain Kinase Is Involved in the Mechanism of Gastrointestinal Dysfunction in Diabetic Rats

“…The contractile and MLC phosphorylation responses to cirazoline of caudal artery strips isolated from type 2 diabetic Goto-Kakizaki rats were significantly reduced compared to those of age-matched Wistar rats [14]. Vehicle-treated diabetic rats demonstrated increased renal MLC phosphorylation as compared to the control animals [15]. Phosphorylation of MLC in the smooth muscle of coronary microvessels was significantly increased in the diabetic Yucatan miniswine compared with the controls [16].…”

Berberine attenuates high glucose-induced fibrosis by activating the G protein-coupled bile acid receptor TGR5 and repressing the S1P2/MAPK signaling pathway in glomerular mesangial cells

“…Berberine exerts renoprotective effects on experimental diabetic models closely associated with glucose and lipid metabolism, antioxidative stress, and anti-inflammation by downregulating the NF-κB, RhoA/ROCK, and SphK1-S1P pathways [18,19]. However, the possible mechanisms have not been fully established.…”

“…In addition, BBR exhibits antioxidant activity and improves insulin resistance and hemodynamics [16,17]. In an experimental diabetic kidney model and high glucose-cultured GMCs, BBR represses the expression of FN, ICAM-1, and TGF-β1 possibly by negatively regulating NF-κB and RhoA/ROCK [18,19]. Furthermore, BBR ameliorates DN by inhibiting the Sphk1/S1P signaling pathway and MAPK activation, lowering AP-1 activity, and eventually deceasing fibronectin overproduction [20][21][22].…”

Blocking VEGF/Caveolin-1 signaling contributes to renal protection of fasudil in streptozotocin-induced diabetic rats

“…Although there was a trend towards decreased blood pressure in the middle-dose fasudil group, this trend was not significant. Komers et al reported that acute administration of fasudil decreased blood pressure in both control and diabetic rats [28] . However, hypertension is the most common adverse event associated with VEGFR-tyrosine kinase inhibitors, and ROCK inhibition blunts sunitinib(VEGF antagonist) -induced hypertension [29] .…”