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bioRxiv · 10.64898/2026.08.12.744527

Loss of Hnf1b in differentiated proximal tubule cells uncovers nephron segment plasticity

Dehghani-Ghobadi, Z.·Chung, E.·Haghighitalab, A.·Sayed, M.·Ahn, C.·Hu, Y.-C.·Lim, H.-W.·Park, J.-S.
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Abstract

HNF1B is a transcription factor required for proximal tubule (PT) specification during kidney development, but whether it is also required to maintain PT identity after differentiation remains unknown. Using PT-specific genetic deletion in mice, we found that loss of Hnf1b in differentiated PT cells causes cyst formation and early postnatal lethality. PT-specific transcriptomic analysis revealed downregulation of PT-specific gene programs, including Hnf4a and PT-enriched transport and metabolic genes. Strikingly, Hnf1b-deficient PT cells ectopically activated podocyte-specific genes, including Wt1 and Nphs1, demonstrating that PT cells retain the capacity to engage alternative nephron segment programs when identity-stabilizing mechanisms are disrupted. In addition, loss of Hnf1b disrupted epithelial integrity, as evidenced by reduced epithelial adhesion gene expression and induction of mesenchymal markers. Wnt/{beta}-catenin signaling was also aberrantly activated, suggesting broader dysregulation of epithelial homeostasis. These findings establish HNF1B as a critical post-specification regulator of PT identity that sustains PT-specific transcriptional programs and actively suppresses alternative segmental identity programs.

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Dehghani-Ghobadi, Z., Chung, E., Haghighitalab, A., Sayed, M., Ahn, C., Hu, Y.-C., Lim, H.-W., Park, J.-S.. 2026-08-17. Loss of Hnf1b in differentiated proximal tubule cells uncovers nephron segment plasticity. https://doi.org/10.64898/2026.08.12.744527

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