β-Arrestin-biased AT1R stimulation promotes extracellular matrix synthesis in renal fibrosis.

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.

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