HNF1B is a transcription factor important for kidney development, with loss-of-function variants causing a rare, monogenic disease. New research has now linked HNFB1 dysfunction to the initiation and perpetuation of chronic kidney disease (CKD) and demonstrated that CKD-associated stresses reciprocally suppress HNF1B activity. “Our findings demonstrate the convergence of mechanistically distinct renal pathologies onto the suppression of HNF1B activity,” explain Fabiola Terzi and Marco Pontoglio. “Importantly, this suppression feeds into a self-sustaining pathogenic feedforward loop in which reduced HNF1B function promotes further epithelial dedifferentiation, fibrosis and tubular dysfunction, which in turn drives deeper HNF1B repression, repositioning HNF1B from a developmental regulator to a central gatekeeper of tubular homeostasis in the adult kidney.”

Terzi and Pontoglio say that the observed severity of renal lesions that developed following HNF1B inactivation in adult mice prompted exploration of the role of HNF1B in CKD. “These observations led us to ask whether mediators of CKD might themselves dampen HNF1B activity,” they explain. “By capturing the very first transcriptional events following HNF1B inactivation, we could distinguish the direct consequences of HNF1B loss from the confounding factors associated with the onset of renal lesions, which enabled us to define a robust HNF1B transcriptional signature.” The identified signature was drastically reduced in various mouse models of CKD. The researchers suggest that this feedforward circuit, in which CKD-associated cellular stresses — notably, albuminuria and interferon-γ — diminish HNF1B transcriptional activity, provides a molecular explanation for the characteristic progression of CKD once a critical threshold of injury is reached, and it may explain why CKD continues to advance even after the initial triggering insult has been controlled. They found that loss of HNF1B expression disrupts the quiescent state of the tubule epithelium, leading to robust cell cycle re-entry, replication stress and activation of a maladaptive program that contributes to kidney fibrosis. An analysis of over 900 human biopsy samples revealed a correlation between reduced HNFB1 signature levels and reduced kidney function.