Loss of genome maintenance accelerates podocyte damage and aging

Abstract

DNA repair is essential for preserving genome integrity and ensures cellular functionality and survival. Podocytes have a very limited regenerative capacity, and their survival is essential to maintain kidney function. While podocyte depletion is a hallmark of glomerular diseases, the mechanisms leading to severe podocyte injury and loss remain largely unclear. We detected perturbations in DNA repair in biopsies from patients with various podocyte-related glomerular diseases and identified single-nucleotide polymorphisms associated with the expression of DNA repair genes in patients suffering from proteinuric kidney disease. Genome maintenance through nucleotide excision repair (NER) proved to be indispensable for podocyte homeostasis. Podocyte-specific knockout of the NER endonuclease co-factor Ercc1 resulted in accumulation of DNA damage, proteinuria, podocyte loss and glomerulosclerosis. The response to this genomic stress was fundamentally different to other cell types, as podocytes activate mTORC1 signaling upon DNA damage in vitro and in vivo.

The insulin / IGF axis is critically important controlling gene transcription in the podocyte

“…However, we also observed a decrease in DNA damage response pathways and histone methylation. As post-mitotic cells with a limited capacity for replenishment, maintaining genomic integrity is crucial for podocyte health (38)(39)(40). Furthermore, altered histone methylation, another feature of the podocyte IR/IGF1R knockdown proteome, has been shown to affect the function of the DNA repair system in podocytes (41).…”