{beta}-Arrestin-biased AT1R stimulation promotes extracellular matrix synthesis in renal fibrosis

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 f...

Source: AJP: Renal Physiology - July 1, 2017 Category: Urology & Nephrology Authors: Wang, Y., Huang, J., Liu, X., Niu, Y., Zhao, L., Yu, Y., Zhou, L., Lu, L., Yu, C. Tags: RESEARCH ARTICLE Source Type: research