HNF1B integrates signals in a feed-forward loop driving kidney disease progression
Chronic kidney disease (CKD), which affects more than 10% of the global population, may continue to progress even after the triggering insult has resolved, suggesting the involvement of self-sustaining mechanisms that remain poorly understood. Here, we identify this molecular circuitry, centered on the transcription factor HNF1B, a key regulator of renal epithelial identity. In adult kidneys, HNF1B loss disrupts epithelial differentiation and quiescence, induces replication stress, and triggers CKD. Conversely, CKD itself epigenetically suppresses HNF1B activity, creating a vicious cycle that amplifies disease progression. In a cohort of 900 patients, lower HNF1B activity correlated with greater CKD severity, linking this mechanism to common forms of the disease. These findings unify rare Mendelian and common complex kidney disorders and identify HNF1B loss as a driver of CKD.
Authors
- Deborah Gaglioti
- Dorien J.M. Peters (ORCID: https://orcid.org/0000-0001-6974-7143)
- Pierre Isnard (ORCID: https://orcid.org/0000-0002-1880-7596)
- Fabiola Terzi (ORCID: https://orcid.org/0000-0001-6107-8125)
- Serge Garbay (ORCID: https://orcid.org/0000-0002-1396-8438)
- Jonathan Levinsohn (ORCID: https://orcid.org/0000-0003-0263-2362)
- Magali Chiral (ORCID: https://orcid.org/0000-0002-8253-7041)
- Katalin Suszták (ORCID: https://orcid.org/0000-0002-1005-3726)
- Michel Leibovici
- Nicolas Zimmermann
- Frank Bienaimé (ORCID: https://orcid.org/0000-0002-8666-2042)
- Munevver Parla Makinistoglu (ORCID: https://orcid.org/0000-0002-2097-860X)
- Marco Pontoglio (ORCID: https://orcid.org/0000-0002-0617-7275)
- Arianna Fiorentino
- Evelyne Fischer (ORCID: https://orcid.org/0000-0002-2420-9832)
- Clément Nguyen
- Camille Cohen
- Armelle Grevellec-Christophorou
Institutions
- Hôpital Necker-Enfants Malades (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Leiden University Medical Center (NL)
- Institut Necker Enfants Malades (FR)
- Hôpital des Enfants (FR)
- University of Pennsylvania (US)
Publication Details
- Journal
- Science
- Published
- 2026-04-16
- DOI
- https://doi.org/10.1126/science.aea3219
- Primary Topic
- Pancreatic function and diabetes
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Fondation Maladies Rares
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Centre National de la Recherche Scientifique
- National Institute of Diabetes and Digestive and Kidney Diseases