该团队确定了这种以转录因子HNF1B为中心的分子电路，HNF1B是肾上皮身份的关键调节因子。在成人肾脏中，HNF1B的丢失破坏上皮分化和静止，诱导复制应激，并引发CKD。相反，CKD本身在表观遗传上抑制HNF1B的活性，形成一个恶性循环，放大疾病进展。在900名患者的队列中，较低的HNF1B活性与更严重的CKD严重程度相关，将这种机制与常见的疾病形式联系起来。这些发现统一了罕见的孟德尔和常见的复杂肾脏疾病，并确定HNF1B缺失是CKD的驱动因素。
据了解，慢性肾脏疾病（CKD）影响全球10%以上的人口，即使在触发性损伤消除后，也可能继续发展，这表明仍不清楚的自我维持机制参与其中。
附：英文原文
Title: HNF1B integrates signals in a feed-forward loop driving kidney disease progression
Author: Pierre Isnard, Munevver Parla Makinistoglu, Michel Leibovici, Jonathan Levinsohn, Nicolas Zimmermann, Camille Cohen, Serge Garbay, Clement Nguyen, Deborah Gaglioti, Magali Chiral, Armelle Grevellec-Christophorou, Arianna Fiorentino, Dorien J. M. Peters, Evelyne Fischer, Frank Bienaimé, Katalin Susztak, Fabiola Terzi, Marco Pontoglio
Issue&Volume: 2026-04-16
Abstract: 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.
DOI: aea3219
Source: https://www.science.org/doi/10.1126/science.aea3219