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.
Competing Interest Statement
The authors have declared no competing interest.