Notch3 orchestrates epithelial and inflammatory responses to promote acute kidney injury

Kidney International
Panagiotis KavvadasChristos Chatziantoniou

Abstract

Acute kidney injury is a major risk factor for subsequent chronic renal and/or cardiovascular complications. Previous studies have shown that Notch3 was de novo expressed in the injured renal epithelium in the early phases of chronic kidney disease. Here we examined whether Notch3 is involved in the inflammatory response and the epithelial cell damage that typifies ischemic kidneys using Notch3 knockout mice and mice with short-term activated Notch3 signaling (N3ICD) in renal epithelial cells. After ischemia/reperfusion, N3ICD mice showed exacerbated infiltration of inflammatory cells and severe tubular damage compared to control mice. Inversely, Notch3 knockout mice were protected against ischemia/reperfusion injury. Renal macrophages derived from Notch3 knockout mice failed to activate proinflammatory cytokines. Chromatin immunoprecipitation analysis of the Notch3 promoter identified NF-κB as the principal inducer of Notch3 in ischemia/reperfusion. Thus, Notch3 induced by NF-κB in the injured epithelium sustains a proinflammatory environment attracting activated macrophages to the site of injury leading to a rapid deterioration of renal function and structure. Hence, targeting Notch3 may provide a novel therapeutic strategy a...Continue Reading

Citations

Sep 11, 2020·Scientific Reports·Susana López-LópezMaría José M Díaz-Guerra
Aug 30, 2020·Journal of the American Society of Nephrology : JASN·Sabine BrandtPeter R Mertens
Oct 23, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Shuiming GuoSong Rong
Dec 29, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Laura Marquez-ExpositoMarta Ruiz-Ortega
Nov 6, 2020·Oxidative Medicine and Cellular Longevity·Cheng YuanXiaoyan Wu

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