R Komers1, T T Oyama, D R Beard, S Anderson. 1. Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR 97239-2940, USA. komersr@ohsu.edu
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.
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-diabeticrats and non-diabetic controls. KEY RESULTS:Diabeticrats 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 diabeticrats. The vasodilator effects of Y27632 and a further decrease in FF, were also detected in diabeticrats pretreated with the angiotensin antagonist losartan. The effects of ROCK inhibitors in diabeticrats 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.
Authors: Radko Komers; William E Schutzer; John F Reed; Jessie N Lindsley; Terry T Oyama; David C Buck; Scott L Mader; Sharon Anderson Journal: Diabetes Date: 2006-06 Impact factor: 9.461
Authors: M Uehata; T Ishizaki; H Satoh; T Ono; T Kawahara; T Morishita; H Tamakawa; K Yamagami; J Inui; M Maekawa; S Narumiya Journal: Nature Date: 1997-10-30 Impact factor: 49.962
Authors: D Strassheim; L G May; K A Varker; H L Puhl; S H Phelps; R A Porter; R S Aronstam; J D Noti; C L Williams Journal: J Biol Chem Date: 1999-06-25 Impact factor: 5.157
Authors: Lin Yao; Surabhi Chandra; Haroldo A Toque; Anil Bhatta; Modesto Rojas; Ruth B Caldwell; R William Caldwell Journal: Cardiovasc Res Date: 2012-12-17 Impact factor: 10.787
Authors: Haroldo A Toque; Kenia P Nunes; Lin Yao; James K Liao; R Clinton Webb; Ruth B Caldwell; R William Caldwell Journal: J Sex Med Date: 2013-04-08 Impact factor: 3.802