Endothelin receptor blockade ameliorates renal injury by inhibition of RhoA/Rho-kinase signalling in deoxycorticosterone acetate-salt hypertensive rats.
OBJECTIVE
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.
Tsung-Ming
TM
Lee
Tun-Hui
TH
Chung
Shinn-Zong
SZ
Lin
Nen-Chung
NC
Chang
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure; D064791:Desoxycorticosterone Acetate / Q000737:chemistry*; D065128:Endothelin Receptor Antagonists / Q000737:chemistry*; D019332:Endothelin-1 / Q000378:metabolism; D005355:Fibrosis / Q000517:prevention & control; D005786:Gene Expression Regulation; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy*; D007668:Kidney / Q000293:injuries; D008297:Male; D011507:Proteinuria / Q000378:metabolism; D011759:Pyrrolidines / Q000737:chemistry; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D017673:Sodium Chloride, Dietary; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D017673:Sodium Chloride, Dietary; D064791:Desoxycorticosterone Acetate; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000077868:Atrasentan