Smad3 promotes AKI sensitivity in diabetic mice via interaction with p53 and induction of NOX4-dependent ROS production.

Redox Biology
Jia-Nan WangXiao-Ming Meng

Abstract

The incidence and severity of acute kidney injury (AKI) is increased yearly in diabetic patients. Although the mechanisms for this remain unclear, the prevention of AKI in diabetic nephropathy is feasible and of value. As we detected highly activation of TGF-β/Smad3 signaling in both human biopsy and mouse model of diabetic nephropathy, we hypothesized that Smad3 activation in diabetic kidneys may increase AKI sensitivity. We tested our hypothesis in vitro using TGF-β type II receptor (TGF-βRII) disrupted tubular epithelial cells (TECs) and in vivo in mice with streptozotocin (STZ)-induced diabetic nephropathy before the induction of ischemia/reperfusion (I/R) injury. We found that high glucose (HG)-cultured TECs showed increased inflammation, apoptosis and oxidative stress following hypoxia/reoxygenation (H/R) injury. Disruption of TGF-βRII attenuated cell injury induced by H/R in HG-treated TECs. Consistently, Smad3 knockdown in diabetic kidney attenuated I/R-induced AKI. Mechanistically, Smad3 binds to p53 and enhances p53 activity in cells treated with HG and H/R, which may lead to TECs apoptosis. Additionally, ChIP assay showed that Smad3 bound with the promoter region of NOX4 and induced ROS production and inflammation. I...Continue Reading

Citations

Nov 24, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Yupeng JiangLijian Tao
Nov 7, 2020·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Ju-Tao YuXiao-Ming Meng
Nov 26, 2020·Drug Design, Development and Therapy·Chuan GuoDehai Yin
Mar 17, 2021·Toxicology and Applied Pharmacology·Wenwen WuZheng Dong
Oct 9, 2021·Frontiers in Cell and Developmental Biology·Xiaoyan WuXiaolei Shi
Oct 12, 2021·Frontiers in Cell and Developmental Biology·Baoyu ChenYifei Feng

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Methods Mentioned

BETA
MDA
biopsy
Assay
ELISA
PCR
light microscopy
fluorescence microscopy
immunoprecipitation
flow cytometry
ChIP

Software Mentioned

Image J
GraphPad Prism
FlowJo

Related Concepts

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis