p53 upregulated by HIF-1α promotes hypoxia-induced G2/M arrest and renal fibrosis in vitro and in vivo

Journal of Molecular Cell Biology
Limin LiuShiren Sun

Abstract

Hypoxia plays an important role in the genesis and progression of renal fibrosis. The underlying mechanisms, however, have not been sufficiently elucidated. We examined the role of p53 in hypoxia-induced renal fibrosis in cell culture (human and rat renal tubular epithelial cells) and a mouse unilateral ureteral obstruction (UUO) model. Cell cycle of tubular cells was determined by flow cytometry, and the expression of profibrogenic factors was determined by RT-PCR, immunohistochemistry, and western blotting. Chromatin immunoprecipitation and luciferase reporter experiments were performed to explore the effect of HIF-1α on p53 expression. We showed that, in hypoxic tubular cells, p53 upregulation suppressed the expression of CDK1 and cyclins B1 and D1, leading to cell cycle (G2/M) arrest (or delay) and higher expression of TGF-β, CTGF, collagens, and fibronectin. p53 suppression by siRNA or by a specific p53 inhibitor (PIF-α) triggered opposite effects preventing the G2/M arrest and profibrotic changes. In vivo experiments in the UUO model revealed similar antifibrotic results following intraperitoneal administration of PIF-α (2.2 mg/kg). Using gain-of-function, loss-of-function, and luciferase assays, we further identified an ...Continue Reading

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Citations

Jul 10, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Craig E HigginsPaul J Higgins
Jul 25, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hao ZhaoLin Sun
Sep 21, 2019·Nucleic Acids Research·Esha MadanRajan Gogna
Mar 25, 2020·Current Opinion in Nephrology and Hypertension·Samuel M-W Yu, Joseph V Bonventre
May 30, 2021·Journal of the American Society of Nephrology : JASN·Sophia Sears, Leah Siskind

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Methods Mentioned

BETA
fluorescence-activated cell sorting
flow cytometry
transfection
ChIP
immunoprecipitations
immunoprecipitation
ELISA
PCR
Assay
protein assay

Software Mentioned

SPSS

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