Loss of genome maintenance is linked to mTOR complex 1 signaling and accelerates podocyte damage
Braun F, Mandel AM, Blomberg L, Wong MN, Chatzinikolaou G, Meyer DH, Reinelt A, Nair V, Akbar-Haase R, McCown PJ, Haas F, Chen H, Rahmatollahi M, Fermin D, Ebbestad R, Slaats GG, Bork T, Schell C, Koehler S, Brinkkoetter PT, Lindenmeyer MT, Cohen CD, Kann M, Unnersjö-Jess D, Bloch W, Sampson MG, Dollé ME, Puelles VG, Kretzler M, Garinis GA, Huber TB, Schermer B, Benzing T, Schumacher B, Kurschat CE (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Book Volume: 10
Article Number: e172370
Journal Issue: 12
DOI: 10.1172/jci.insight.172370
Abstract
DNA repair is essential for preserving genome integrity. Podocytes, postmitotic epithelial cells of the kidney filtration unit, bear limited regenerative capacity, yet their survival is indispensable for kidney health. Podocyte loss is a hallmark of the aging process and of many diseases, but the underlying factors remain unclear. We investigated the consequences of DNA damage in a podocyte-specific knockout mouse model for DNA excision repair protein Ercc1 and in cultured podocytes under genomic stress. Furthermore, we characterized DNA damage-related alterations in mouse and human renal tissue of different ages and patients with minimal change disease and focal segmental glomerulosclerosis. Ercc1 knockout resulted in accumulation of DNA damage and ensuing albuminuria and kidney disease. Podocytes reacted to genomic stress by activating mTOR complex 1 (mTORC1) signaling in vitro and in vivo. This was abrogated by inhibiting DNA damage signaling through DNA-dependent protein kinase (DNA-PK) and ataxia teleangiectasia mutated (ATM) kinases, and inhibition of mTORC1 modulated the development of glomerulosclerosis. Perturbed DNA repair gene expression and genomic stress in podocytes were also detected in focal segmental glomerulosclerosis. Beyond that, DNA damage signaling occurred in podocytes of healthy aging mice and humans. We provide evidence that genome maintenance in podocytes is linked to the mTORC1 pathway and is involved in the aging process as well as the development of glomerulosclerosis.
Involved external institutions
Universitätsklinikum Hamburg-Eppendorf (UKE)
Germany (DE)
FORTH Institute of Molecular Biology and Biotechnology (IMBB) / Ινστιτούτο Μοριακής Βιολογίας και Βιοτεχνολογίας
Greece (GR)
University of Michigan
United States (USA) (US)
Karolinska Institute
Sweden (SE)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Deutsche Sporthochschule Köln
Germany (DE)
Boston Children's Hospital
United States (USA) (US)
Netherlands National Institute for Public Health and the Environment / Rijksinstituut voor Volksgezondheid en Milieu (RIVM)
Netherlands (NL)
Germany (DE)
FORTH Institute of Molecular Biology and Biotechnology (IMBB) / Ινστιτούτο Μοριακής Βιολογίας και Βιοτεχνολογίας
Greece (GR)
University of Michigan
United States (USA) (US)
Karolinska Institute
Sweden (SE)
Albert-Ludwigs-Universität Freiburg
Germany (DE)
Deutsche Sporthochschule Köln
Germany (DE)
Boston Children's Hospital
United States (USA) (US)
Netherlands National Institute for Public Health and the Environment / Rijksinstituut voor Volksgezondheid en Milieu (RIVM)
Netherlands (NL)
How to cite
APA:
Braun, F., Mandel, A.M., Blomberg, L., Wong, M.N., Chatzinikolaou, G., Meyer, D.H.,... Kurschat, C.E. (2025). Loss of genome maintenance is linked to mTOR complex 1 signaling and accelerates podocyte damage. JCI Insight, 10(12). https://doi.org/10.1172/jci.insight.172370
MLA:
Braun, Fabian, et al. "Loss of genome maintenance is linked to mTOR complex 1 signaling and accelerates podocyte damage." JCI Insight 10.12 (2025).
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