title: Aldosterone induction of hepatic stellate cell contraction through activation of RhoA/ROCK-2 signaling pathway.
abstract: The RhoA/ROCK-2 signaling pathway is necessary for activated hepatic stellate cell (HSC) contraction. HSC contraction plays an important role in the pathogenesis of cirrhosis and portal hypertension. This study investigated whether aldosterone contributes to HSC contraction by activation of the RhoA/ROCK-2 signaling pathway. Primary HSCs were isolated from Sprague-Dawley rats via in situ pronase/collagenase perfusion. We found that aldosterone enhanced the contraction of a collagen lattice seeded with HSCs. This induced contraction was suppressed by the mineralcorticoid receptor (MR) inhibitor spironolactone, the ROCK-2 inhibitor Y27632, and the angiotensin II type 1 receptor (AT(1)R) inhibitor irbesartan. Moreover, actin fiber staining showed that aldosterone significantly increased actin fiber formation in HSCs. Pre-incubating with spironolactone, Y27632, or irbesartan inhibited the aldosterone-induced actin fiber reorganization. Molecularly, the effect of aldosterone on activation of HSC contraction was mediated by phosphorylated myosin light chain (P-MLC) through the RhoA/ROCK-2 signaling pathway. All these inhibitors had the ability to block aldosterone-induced protein expressions in the RhoA/ROCK-2/P-MLC cascade in HSCs. Taken together, our current study suggests that aldosterone induces contraction of activated HSCs through the activation of the RhoA/ROCK-2 signaling pathway. This finding may provide a potential therapeutic target for control of cirrhosis and portal hypertension.
authors.affiliation: Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Hongli
authors.initials: H
authors.lastname: Ji
authors.forename: Ying
authors.initials: Y
authors.lastname: Meng
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Luo
authors.forename: Pingsheng
authors.initials: P
authors.lastname: Wu
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
authors.forename: Zhenshu
authors.initials: Z
authors.lastname: Zhang
authors.forename: Xu
authors.initials: X
authors.lastname: Li
mesh_terms: D000450:Aldosterone / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D048429:Cell Size / Q000187:drug effects*; D002478:Cells, Cultured; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D000077405:Irbesartan; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists; D018994:Myosin Light Chains / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013148:Spironolactone / Q000494:pharmacology; D022502:Stress Fibers / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D000451:Mineralocorticoid Receptor Antagonists; D018994:Myosin Light Chains; D011725:Pyridines; D013777:Tetrazoles; C108830:Y 27632; D013148:Spironolactone; D000450:Aldosterone; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000077405:Irbesartan