Lysyl oxidase promotes renal fibrosis via accelerating collagen cross-link driving by β-arrestin/ERK/STAT3 pathway

Xiaoqin Zhang, Wenqian Zhou, Yangyang Niu, Saiya Zhu, Yingying Zhang, Xiaogang Li, Chen Yu

Research output: Contribution to journalArticlepeer-review

Abstract

Lysyl oxidase (LOX) is a copper-dependent monoamine oxidase whose primary function is the covalent cross-linking of collagen in the extracellular matrix (ECM). Evidence has shown that LOX is associated with cancer and some fibrotic conditions. We recently found that serum LOX is a potential diagnostic biomarker for renal fibrosis, but the mechanism by which LOX is regulated and contributes to renal fibrosis remains unknown. The current study demonstrates the following: (1) LOX expression was increased in fibrotic kidneys including ischemia-reperfusion injury-(IRI-), unilateral ureteral obstruction-(UUO-), and folic acid- (FA-) induced fibrotic kidneys as well as in the paraffin-embedded sections of human kidneys from the patients with renal fibrosis. (2) The increasing deposition and cross-linking of collagen induced by LOX was observed in IRI-, UUO- and FA-kidneys. (3) LOX was regulated by the β-arrestin-ERK-STAT3 pathway in renal fibrosis. STAT3 was the downstream of AT1R-β-arrestin-ERK, ERK entered the nucleus and activated STAT3-pY705 but not STAT3-pS727. (4) STAT3 nuclear subtranslocation and binding to the LOX promoter may be responsible for the upregulation of LOX expression. (5) Pharmacologic inhibition of LOX with BAPN in vivo inhibited the upregulation of LOX, decreased collagen over cross-linking and ameliorated renal fibrosis after ischemic injury. Collectively, these observations suggest that LOX plays an essential role in the development of renal fibrosis by catalyzing collagen over cross-linking. Thus, strategies targeting LOX could be a new avenue in developing therapeutics against renal fibrosis.

Original languageEnglish (US)
Article numbere22427
JournalFASEB Journal
Volume36
Issue number8
DOIs
StatePublished - Aug 2022

Keywords

  • ERK/STAT3
  • LOX
  • renal fibrosis
  • STAT3-pY705
  • β-arrestin pathway

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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