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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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COL4A3 Mutation Induced Podocyte Apoptosis by Dysregulation of NADPH Oxidase 4 and MMP-2

Jun Tong1, Qimin Zheng1, Xiangchen Gu1

  • 1Department of Nephrology, Institute of Nephrology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China.

Kidney International Reports
|September 14, 2023
PubMed
Abstract

Insights

NOX4 inhibition reduces podocyte apoptosis by downregulating MMP-2 in Alport syndrome (AS) patients with COL4A3 mutations. This study reveals a novel NOX4/MMP-2 pathway contributing to AS progression.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Podocyte apoptosis is a key driver of Alport syndrome (AS) progression, particularly in cases involving COL4A3 mutations.
  • Understanding the molecular mechanisms underlying podocyte apoptosis in AS is crucial for developing targeted therapies.

Purpose of the Study:

  • To investigate the specific mechanism by which COL4A3 mutations lead to podocyte apoptosis.
  • To identify key molecular players and pathways involved in podocyte injury in autosomal dominant AS (ADAS).

Main Methods:

  • Microarray analysis of glomeruli from ADAS patients and controls.
  • Creation of mutant human podocytes (p.C1616Y) and mouse models (p.C1615Y).
  • Validation of differentially expressed genes (DEGs) and pathway analysis using qPCR, immunohistochemistry, and Western blot, with and without NOX4 and MMP-2 inhibitors.

Main Results:

  • Microarray identified upregulated NOX4, MMP-2, and apoptosis-related genes in ADAS.
  • NOX4 inhibition abrogated podocyte apoptosis and decreased MMP-2 expression both in vitro and in vivo, improving renal pathology.
  • MMP-2 inhibition attenuated podocyte apoptosis without affecting NOX4 levels.

Conclusions:

  • NOX4 induces podocyte apoptosis via MMP-2 regulation in COL4A3-mutation-associated AS.
  • This NOX4/MMP-2 pathway offers a potential therapeutic target for ADAS.
Keywords:
COL4A3 mutationMMP-2NADPH Oxidase 4Podocyte Apoptosis

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