HNF1B integrates signals in a feed-forward loop driving kidney disease progression
April 16, 2026 - Science

The INEM teams Epigenetics and Development led by Marco Pontoglio and Mechanisms and Therapeutic Strategies of Chronic Kidney Disease led by Fabiola Terzi, in collaboration with Katalin Susztak (University of Pennsylvania, USA), report the identification of a key molecular mechanism driving the progression of chronic kidney disease (CKD), a condition affecting more than 10% of the global population.

Initiated by Pierre Isnard and Parla Makinistoglu, this study published in Science, investigated the role of the transcription factor HNF1B, known for its essential function during kidney development. Using mouse models and human data, they demonstrate that loss of HNF1B activity in renal tubular epithelial cells leads to rapid and severe CKD, characterized by tubular atrophy, fibrosis, inflammation, and progressive renal failure.

Mechanistically, HNF1B deficiency disrupts epithelial cell identity and triggers inappropriate cell cycle re-entry in normally quiescent tubular cells. This results in replication stress, DNA damage, and cell death, ultimately contributing to tissue degeneration and fibrosis. Importantly, the authors identify a transcriptional signature of HNF1B that is suppressed at very early stages in multiple models of kidney injury, even before the appearance of detectable lesions.

The study further shows that common CKD-associated stresses, such as inflammation or albuminuria, actively repress HNF1B activity through epigenetic mechanisms. Analysis of nearly 900 human kidney biopsies confirms that reduced HNF1B activity strongly correlates with disease severity, linking this mechanism to a wide range of kidney pathologies.

Together, these findings reveal the existence of a self-reinforcing feed-forward loop in which loss of HNF1B promotes kidney disease, while disease-associated stress further suppresses HNF1B activity. This mechanism provides a unifying framework connecting rare genetic kidney disorders and common forms of CKD, and identifies HNF1B as a potential therapeutic target to slow or alter disease progression.

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Image credits: Marco Pontoglio