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Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in deoxycorticosterone acetate-salt hypertensive rats

Lee, Tsung-Minga,b; Chung, Tun-Huic; Lin, Shinn-Zongd,e; Chang, Nen-Chungf,g

doi: 10.1097/HJH.0000000000000092
ORIGINAL PAPERS: Pathophysiological aspects

Purpose of review: Excessive production of fibrosis is a feature of hypertension-induced renal injury. Activation of RhoA/Rho-kinase (ROCK) axis has been shown in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed whether selective endothelin receptor blockers can attenuate renal fibrosis by inhibiting RhoA/ROCK axis in DOCA-salt rats.

Methods: At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 4 weeks: vehicle, ABT-627 (endothelin-A receptor inhibitor) and A192621 (endothelin-B receptor inhibitor).

Results: DOCA-salt was characterized by increased blood pressure, decreased renal function, increased proteinuria, increased glomerulosclerosis and tubulointerstitial fibrosis with myofibroblast accumulation, increased renal endothelin-1 levels and RhoA activity along with increased expression of connective tissue growth factor at both mRNA and protein levels as compared with uninephrectomized control male Wistar rats. Treatment with a selective mineralocorticoid receptor antagonist, eplerenone, ameliorated proteinuria. Impaired renal function and histological changes were overcome by treatment with ABT-627, but not with A192621. The beneficial effects of bosentan, a nonspecific endothelin receptor blocker, on proteinuria, RhoA activity, and connective tissue growth factor levels were similar to ABT-627. Furthermore, in an isolated perfuse kidney, a RhoA inhibitor, C3 exoenzyme, and two ROCK inhibitors, fasudil and Y-27632, significantly attenuated connective tissue growth factor levels.

Conclusions: These results indicate that DOCA-salt elevates renal endothelin-1 levels and RhoA activity via activation of mineralocorticoid receptor, resulting in renal fibrosis and proteinuria. Endothelin-A receptor blockade can attenuate DOCA-salt-induced renal fibrosis probably through the inhibition of RhoA/ROCK activity and connective tissue growth factor expression.

aDepartment of Medicine, Cardiology Section, Tainan Municipal An-Nan Hospital-China Medical University, Tainan

bDepartment of Medicine, China Medical University, Taichung

cDepartment of Medicine, School of Medicine, Fu-Jen Catholic University

dDepartment of Neurosurgery, China Medical University Beigan Hospital, Yunlin

eDepartment of Neurosurgery, Tainan Municipal An-Nan Hospital-China Medical University, Tainan

fDivision of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital

gDepartment of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan

Correspondence to Dr Nen-Chung Chang, Department of Internal Medicine, School of Medicine, Taipei Medical University, 250, Wu-Hsing Street, Taipei, 11031, Taiwan. E-mail: ncchang@tmu.edu.tw

Abbreviations: α-SMA, α-smooth muscle actin; Ccr, creatinine clearance; CTGF, connective tissue growth factor; DOCA, deoxycorticosterone acetate; ET-1, endothelin-1; GDP, guanosine diphosphate; GTP, guanosine triphosphate; PAS, periodic acid Schiff; ROCK, Rho-kinase; RT-PCR, real-time quantitative reverse transcription-PCR; Unx, uninephrectomized

Received 17 March, 2013

Accepted 27 November, 2013

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