HNF1B integrates signals in a feed-forward loop driving kidney disease progression [RNAseq_P60d2]

While GWAS have identified common variants, rare variants and gene-environment interactions likely play a major role. HNF1B, a transcription factor essential for kidney development, is also a cause of monogenic CKD but its function in adult kidneys remains unclear.

Here, we show that HNF1B loss in adult mouse kidneys induces rapid CKD with epithelial dedifferentiation, aberrant cell cycle re-entry, and replicative stress. Strikingly, suppression of the HNF1B transcriptional program is observed across multiple human and experimental CKD models, independent of cause. These findings position HNF1B as a central regulator of renal epithelial integrity and reveal a feed-forward mechanism in which HNF1B dysfunction contributes to and is reinforced by CKD progression.