Related Experiment Video

Updated: May 22, 2025

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
07:15

Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway

Published on: August 23, 2024

303

Loss of genome maintenance is linked to mTOR complex 1 signaling and accelerates podocyte damage

Fabian Braun1,2,3,4, Amrei M Mandel1,5,6, Linda Blomberg1,5

  • 1Department II of Internal Medicine and Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

JCI Insight
|May 20, 2025
PubMed

Insights

Genome maintenance is crucial for kidney health. DNA damage in podocytes activates mTORC1 signaling, contributing to aging and glomerulosclerosis, highlighting a link between DNA repair and kidney disease.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Genetics

Background:

  • Podocytes, crucial for kidney filtration, are post-mitotic and have limited regeneration.
  • Podocyte loss is linked to aging and kidney diseases, but underlying mechanisms are unclear.
  • DNA repair is vital for maintaining genome integrity.

Purpose of the Study:

  • To investigate the role of DNA damage and repair in podocyte aging and kidney disease.
  • To explore the connection between DNA damage, mTORC1 signaling, and glomerulosclerosis.
  • To identify potential therapeutic targets for kidney diseases involving podocyte damage.

Main Methods:

  • Generated a podocyte-specific Ercc1 knockout mouse model.
  • Utilized cultured podocytes under genomic stress.
  • Analyzed mouse and human renal tissues from aging individuals and patients with kidney diseases.
  • Investigated DNA damage signaling pathways, including DNA-PK and ATM kinases.
  • Assessed mTORC1 pathway activation and its modulation by inhibiting DNA damage signaling.

Main Results:

  • Ercc1 knockout led to DNA damage accumulation, albuminuria, and kidney disease in mice.
  • Podocytes activated mTORC1 signaling in response to genomic stress.
  • Inhibition of DNA damage signaling or mTORC1 modulated glomerulosclerosis development.
  • Increased DNA damage and altered DNA repair gene expression were observed in focal segmental glomerulosclerosis.
  • DNA damage signaling was present in aging mouse and human podocytes.

Conclusions:

  • Genome maintenance in podocytes is intrinsically linked to the mTORC1 pathway.
  • This link plays a role in the podocyte aging process.
  • The findings suggest a mechanism contributing to the development of glomerulosclerosis.
  • Targeting DNA repair and mTORC1 pathways may offer therapeutic strategies for kidney diseases.
Keywords:
AgingCell biologyChronic kidney diseaseDNA repairNephrology

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