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Kidney Week

Abstract: PO0638

Investigating LOX and Its Role in AT1R/β-Arrestin Biased Signaling Pathway-Induced Renal Interstitial Fibrosis

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms


  • Zhang, Xiaoqin, Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China, Shanghai, China
  • Yu, Chen, Department of Nephrology, Tongji Hospital, Tongji University, Shanghai, China, Shanghai, China

Group or Team Name

  • Tongji University, Shanghai, China

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-arrestin pathway


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.


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.


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.


  • Government Support - Non-U.S.