title: β-Arrestin-biased AT1R stimulation promotes extracellular matrix synthesis in renal fibrosis.
abstract: The renin-angiotensin system plays a critical role in the progression of renal fibrosis. Angiotensin II type 1 receptor (AT1R) belongs to the B family of the G protein-coupled receptor (GPCR) family. β-Arrestins are known as negative regulators of GPCRs. Recently, β-arrestins have been found to regulate multiple intracellular signaling pathways independent of G proteins. In this study we investigated the role of β-arrestins in regulating extracellular matrix (ECM) synthesis in renal fibrosis. The rat kidney fibroblast cell line (NRK-49F) was treated with the β-arrestin biased agonist [1-sar, 4, 8-ile]angiotensin II (SII), which does not initiate AT1R-G protein signaling. The cells were transfected with recombinant adenoviruses expressing β-arrestin-2 gene or small-interfering RNA (siRNA) targeting β-arrestin-2. The unilateral ureteral obstruction (UUO) model was used in vivo. mRNA and protein levels of β-arrestin-2, not β-arrestin-1, were significantly upregulated in the UUO kidney tissues. SII induced the tight binding of β-arrestin-2 with AT1R. SII increased the synthesis of collagen I and fibronectin in NRK-49F, which were abolished when pretreated with candesartan (AT1R blocker). Transfection of siRNA targeting β-arrestin-2 decreased the effects of SII on ECM synthesis. Overexpression of β-arrestin-2 enhanced SII-stimulated ECM synthesis. SII induced ERK1/2 phosphorylation in NRK-49F. Transfection of siRNA targeting β-arrestin-2 inhibited ERK phosphorylation. Overexpression of β-arrestin-2 increased ERK1/2 phosphorylation. Our study first showed that AT1R-β-arrestin-2 pathway signaling plays an important role in renal fibrosis, although it was previously believed that the AT1R-G protein pathway plays a major role. Targeting β-arrestin-2 may be a potential therapeutic agent for renal fibrosis.
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and.
authors.forename: Yandao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and.
authors.forename: Jieli
authors.initials: J
authors.lastname: Huang
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and.
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Niu
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and.
authors.forename: Liqin
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and yuchen@tongji.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Limin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Nephrology, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; and yuchen@tongji.edu.cn.
authors.forename: Chen
authors.initials: C
authors.lastname: Yu
mesh_terms: D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002460:Cell Line; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007674:Kidney Diseases / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014517:Ureteral Obstruction / Q000150:complications; D000071559:beta-Arrestin 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000071560:beta-Arrestin 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; C000605255:Arrb1 protein, mouse; C000605256:Arrb1 protein, rat; C000605258:Arrb2 protein, mouse; C000605257:Arrb2 protein, rat; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D024042:Collagen Type I; D005353:Fibronectins; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; C502020:angiotensin II, Sar(1)-Ile(4)-Ile(8)-; D000071559:beta-Arrestin 1; D000071560:beta-Arrestin 2; D000804:Angiotensin II; C535149:Mapk1 protein, rat; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C081643:candesartan
keywords: [1-sar, 4, 8-ile]angiotensin II; angiotensin II type I receptor; extracellular matrix; extracellular signal-regulated kinase 1/2; β-arrestins