Loss of genome maintenance accelerates podocyte damage

AbstractBackgroundDNA repair is essential for preserving genome integrity and ensuring 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 many glomerular diseases, the mechanisms leading to severe podocyte injury and loss remain unclear.MethodsWe investigated DNA repair mechanisms in glomerular diseases by gene expression analysis of human kidney biopsies. Using a constitutive and an inducible podocyte-specificErcc1knockout mouse model, we assessed the influence of disrupted NERin vivo, complemented by mechanisticalin vitrostudies of induced DNA damage in cultured podocytes. Furthermore, we characterized DNA damage-related alterations in aged mice and human renal tissue of different age groups as well as in minimal change disease (MCD) and Focal segmental glomerulosclerosis (FSGS) patient biopsies.ResultsWe detected perturbed NER gene expression in nuclei of podocytes in FSGS as well as aberrations of DNA repair genes in biopsies of patients with various podocyte-related glomerular diseases. Genome maintenance through NER proved to be indispensable for podocyte homeostasis. Podocyte-specific accumulation of DNA damage through the knockout of the NER endonuclease co-factor Ercc1 resulted in proteinuria, podocyte loss, glomerulosclerosis, and renal insufficiency. The response to this genomic stress was fundamentally different to the pattern reported in other cell types, as podocytes activated mTORC1 signaling upon DNA damagein vitroandin vivo. The induced mTORC1 activation was abrogated by inhibiting DNA damage response through DNA-PK and ATMin vitro. Moreover, pharmacological inhibition of mTORC1 ameliorated the development of glomerulosclerosis in NER-deficient mice.ConclusionDisruption of DNA damage response pathways seems to be a uniform response in several glomerulopathies. Accumulation of DNA damage in podocytes results in glomerulosclerosis and activates mTORC1 signaling.Translational statementGrowing evidence suggests that perturbations in genome maintenance play a role in glomerulopathies. The authors have identified several DNA repair genes to be differentially expressed in glomerular diseases in human kidney biopsies and observed dramatic differences in nucleotide excision repair (NER) gene expression in focal segmental glomerulosclerosis (FSGS) podocytes.In vivoandin vitroanalyses in murine podocytes uncovered accumulation of DNA damage through disruption of NER to result in podocyte loss with glomerulosclerosis and to activate the mTORC1 pathway. Similar results were identified in FSGS patient biopsies as well as in renal specimens of human and murine aging. These findings reveal that DNA damage and its repair pathways are crucial for podocyte maintenance and for the development of glomerulosclerosis, potentially serving as therapeutic targets in the future.