Abstract
Abstract Background and Aims We studied the downstream and mechanism of β-arrestins signaling in renal fibrosis process and the role of lysyl oxidase (LOX) in the AT1R-β-arrestins pathway. Method The mechanism of β-arrestins signaling was studied in normal rat kidney tubule epithelial cells (NRK-52E) treated with SII in vitro. BAPN or placebo was administered during ischemia reperfusion (IR)-induced fibrosis progression. Collagen crosslinking and fibrosis progression were assessed histologically and biochemically. Results The mRNA and protein levels of β-arrestin-1 and β-arrestin-2 were significantly upregulated in renal fibrosis model both in vitro and in vivo. SII activated the ERK-STAT3 PY705 but not STAT3-Try727 in nucleus of NRK-52E cells, which effects were abolished when transfection of siRNA targeting β-arrestin-1 and β-arrestin-2 or pretreated with PD98059 (MEK inhibitor). LOX was strongly induced in fibrotic kidney and NRK-52E cells treated with SII. Active LOX significantly increased collagen crosslinking. In established IR-28d renal fibrosis, LOX inhibition promoted fibrosis reversal and with a 25% decrease insoluble collagen. Gene silencing of β-arrestin-1 + 2 or STAT3 apparently inhibited SII-induced LOX expression in vitro. Besides, chromatin immunoprecipitation (ChIP) assay clearly demonstrating the interaction between STAT3 and the LOX promoter, which indicated LOX is a direct target gene of SII-β-arrestins-STAT3 signaling. Conclusion The ERK/STAT3 was downstream of AT1R-β-arrestins, ERK entered the nucleus and activated STAT3-PY705. LOX mediates collagen crosslinking and fibrotic matrix stabilization during renal fibrosis via the AT1R-β-arrestins-ERK-STAT3-PY705 signaling. By blocking this profibrotic pathway, therapeutic LOX inhibition attenuates the fibrosis and suggesting target the LOX has significant potency for the treatment of patients with fibrotic kidney disorders.
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