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HNF1B integrates signals in a feed-forward loop driving kidney disease progression.

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Title: HNF1B integrates signals in a feed-forward loop driving kidney disease progression.
Authors: Isnard, Pierre (AUTHOR), Makinistoglu, Munevver Parla (AUTHOR), Leibovici, Michel (AUTHOR), Levinsohn, Jonathan (AUTHOR), Zimmermann, Nicolas (AUTHOR), Cohen, Camille (AUTHOR), Garbay, Serge (AUTHOR), Nguyen, Clement (AUTHOR), Gaglioti, Deborah (AUTHOR), Chiral, Magali (AUTHOR), Grevellec-Christophorou, Armelle (AUTHOR), Fiorentino, Arianna (AUTHOR), Peters, Dorien J. M. (AUTHOR), Fischer, Evelyne (AUTHOR), Bienaimé, Frank (AUTHOR), Susztak, Katalin (AUTHOR), Terzi, Fabiola (AUTHOR), Pontoglio, Marco (AUTHOR)
Source: Science. 4/16/2026, Vol. 392 Issue 6795, p1-15. 15p.
Subjects: Hepatocyte nuclear factors, Transcription factors, Replication fork, Chronic kidney failure, Renal fibrosis, Kidney tubules, Cell cycle, Epigenetics
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. Editor's summary: Chronic kidney disease is very common all over the world, and its progression is usually irreversible past a certain threshold of renal impairment regardless of the underlying cause. Most cases of chronic renal disease are multifactorial, but there are some proteins involved in monogenic kidney disease that may provide insight into the mechanisms of normal kidney function and kidney disorders. Isnard et al. focused on one such protein, hepatocyte nuclear factor 1 beta (HNF1B), one of the most common monogenic causes of disordered kidney development. The authors found alterations in HNF1B function in more common types of kidney disease as well, and showed that mice with a deficiency of this protein develop kidney disease characterized by aberrant cell cycle reentry and progressive abnormalities similar to those seen in human patients. —Yevgeniya Nusinovich INTRODUCTION: Chronic kidney disease (CKD) affects more than 10% of the global population and is characterized by an inexorable decline in renal function, regardless of the triggering insult. A defining feature of CKD is its self-perpetuating nature: Once established, kidney injury progresses even when the original trigger has resolved. Identifying the molecular circuits that maintain this pathological state is essential to understand disease progression and to design effective therapeutic strategies. RATIONALE: HNF1B is a transcription factor essential for renal development. Heterozygous loss-of-function mutations in HNF1B cause autosomal dominant tubulointerstitial kidney disease, a rare monogenic disorder whose renal histopathology phenocopies that of common CKD. This phenotypic convergence suggested that HNF1B dysfunction might represent a shared mechanism linking rare genetic kidney diseases to more prevalent, multifactorial CKD. We hypothesized that HNF1B activity may be progressively suppressed during CKD, creating a feed-forward loop that may drive disease progression. RESULTS: Using a mouse model, we found that postnatal inactivation of Hnf1b in renal tubular epithelial cells led to very rapid and severe CKD, characterized by tubular atrophy, interstitial fibrosis, inflammation, and progressive renal failure. Loss of Hnf1b disrupted epithelial differentiation and triggered abrupt cell cycle reentry in normally quiescent tubular cells. This unscheduled proliferation caused replication stress, DNA damage, apoptosis, and senescence, leading to CKD. Pharmacological inhibition of aberrant cell cycle entry using the CDK4/6 inhibitor palbociclib slightly mitigated tubular injury and fibrosis in Hnf1b-deficient mice, demonstrating that replication stress participates in the progression of the disease downstream of HNF1B loss. To identify the earliest molecular consequences of HNF1B loss, we defined the transcriptional signature of HNF1B, before the onset of renal lesions. This signature was markedly reduced in multiple preclinical models of CKD initiated by HNF1B-independent insults, including subtotal nephrectomy, Alport syndrome, ischemia-reperfusion injury, nephrotic syndrome, and unilateral ureteral obstruction. Notably, the suppression of HNF1B activity occurred before the appearance of any overt histological damage and was correlated with failed epithelial repair following acute kidney injury. Mechanistically, we found that common CKD-associated stresses, including albuminuria and interferon-γ, reduced HNF1B transcriptional activity in renal tubular cells. Single-cell transcriptomic and chromatin accessibility analyses revealed that injured and maladaptively repairing tubular cells exhibited decreased accessibility at HNF1B binding sites, linking epithelial stress to epigenetic repression of HNF1B function. Finally, analysis of human kidney transcriptomic datasets, including nearly 900 biopsies spanning a wide range of CKD severity, revealed that reduced HNF1B target gene expression strongly correlated with declining kidney function, tubular atrophy, and fibrosis. These findings establish HNF1B activity as a molecular determinant of CKD severity in humans. CONCLUSION: Our results demonstrate that HNF1B is a gatekeeper of renal tubular homeostasis whose loss initiates and perpetuates CKD. We uncover a self-reinforcing feed-forward loop in which HNF1B deficiency drives CKD, whereas CKD-associated stresses epigenetically suppress HNF1B activity. This mechanism bridges rare monogenic kidney disorders and common forms of CKD and provides a conceptual framework for understanding the relentless nature of CKD. Restoring HNF1B activity may represent a therapeutic strategy to alter the trajectory of CKD. Epigenetic repression of HNF1B, induced by renal tubular stress, drives CKD progression.: Inactivation of Hnf1b in quiescent renal tubular epithelial cells induces rapid dedifferentiation and abrupt cell cycle reentry, leading to replication stress, cell death, and ultimately, severe chronic kidney disease (CKD). To capture the earliest molecular events preceding tissue damage, we combined ChIP-seq and transcriptomic analyses in kidneys from Hnf1b mutant mice 2 days after gene inactivation, before the appearance of histological lesions. This analysis identified a prelesional HNF1B transcriptional signature, which was markedly reduced in multiple mouse models of CKD as well as in human CKD even before lesion development. Analysis of a cohort of ~900 patients revealed that reduced expression of this signature strongly correlates with renal function decline. CKD-associated stresses, including albuminuria and interferon-γ, diminished HNF1B transcriptional activity in renal tubular cells. Together, these findings uncover a feed-forward pathogenic loop in which HNF1B deficiency promotes CKD progression, whereas CKD-associated stresses further suppress HNF1B activity through epigenetic mechanisms. [ABSTRACT FROM AUTHOR]
Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: HNF1B integrates signals in a feed-forward loop driving kidney disease progression.
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  Data: 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. Editor's summary: Chronic kidney disease is very common all over the world, and its progression is usually irreversible past a certain threshold of renal impairment regardless of the underlying cause. Most cases of chronic renal disease are multifactorial, but there are some proteins involved in monogenic kidney disease that may provide insight into the mechanisms of normal kidney function and kidney disorders. Isnard et al. focused on one such protein, hepatocyte nuclear factor 1 beta (HNF1B), one of the most common monogenic causes of disordered kidney development. The authors found alterations in HNF1B function in more common types of kidney disease as well, and showed that mice with a deficiency of this protein develop kidney disease characterized by aberrant cell cycle reentry and progressive abnormalities similar to those seen in human patients. —Yevgeniya Nusinovich INTRODUCTION: Chronic kidney disease (CKD) affects more than 10% of the global population and is characterized by an inexorable decline in renal function, regardless of the triggering insult. A defining feature of CKD is its self-perpetuating nature: Once established, kidney injury progresses even when the original trigger has resolved. Identifying the molecular circuits that maintain this pathological state is essential to understand disease progression and to design effective therapeutic strategies. RATIONALE: HNF1B is a transcription factor essential for renal development. Heterozygous loss-of-function mutations in HNF1B cause autosomal dominant tubulointerstitial kidney disease, a rare monogenic disorder whose renal histopathology phenocopies that of common CKD. This phenotypic convergence suggested that HNF1B dysfunction might represent a shared mechanism linking rare genetic kidney diseases to more prevalent, multifactorial CKD. We hypothesized that HNF1B activity may be progressively suppressed during CKD, creating a feed-forward loop that may drive disease progression. RESULTS: Using a mouse model, we found that postnatal inactivation of Hnf1b in renal tubular epithelial cells led to very rapid and severe CKD, characterized by tubular atrophy, interstitial fibrosis, inflammation, and progressive renal failure. Loss of Hnf1b disrupted epithelial differentiation and triggered abrupt cell cycle reentry in normally quiescent tubular cells. This unscheduled proliferation caused replication stress, DNA damage, apoptosis, and senescence, leading to CKD. Pharmacological inhibition of aberrant cell cycle entry using the CDK4/6 inhibitor palbociclib slightly mitigated tubular injury and fibrosis in Hnf1b-deficient mice, demonstrating that replication stress participates in the progression of the disease downstream of HNF1B loss. To identify the earliest molecular consequences of HNF1B loss, we defined the transcriptional signature of HNF1B, before the onset of renal lesions. This signature was markedly reduced in multiple preclinical models of CKD initiated by HNF1B-independent insults, including subtotal nephrectomy, Alport syndrome, ischemia-reperfusion injury, nephrotic syndrome, and unilateral ureteral obstruction. Notably, the suppression of HNF1B activity occurred before the appearance of any overt histological damage and was correlated with failed epithelial repair following acute kidney injury. Mechanistically, we found that common CKD-associated stresses, including albuminuria and interferon-γ, reduced HNF1B transcriptional activity in renal tubular cells. Single-cell transcriptomic and chromatin accessibility analyses revealed that injured and maladaptively repairing tubular cells exhibited decreased accessibility at HNF1B binding sites, linking epithelial stress to epigenetic repression of HNF1B function. Finally, analysis of human kidney transcriptomic datasets, including nearly 900 biopsies spanning a wide range of CKD severity, revealed that reduced HNF1B target gene expression strongly correlated with declining kidney function, tubular atrophy, and fibrosis. These findings establish HNF1B activity as a molecular determinant of CKD severity in humans. CONCLUSION: Our results demonstrate that HNF1B is a gatekeeper of renal tubular homeostasis whose loss initiates and perpetuates CKD. We uncover a self-reinforcing feed-forward loop in which HNF1B deficiency drives CKD, whereas CKD-associated stresses epigenetically suppress HNF1B activity. This mechanism bridges rare monogenic kidney disorders and common forms of CKD and provides a conceptual framework for understanding the relentless nature of CKD. Restoring HNF1B activity may represent a therapeutic strategy to alter the trajectory of CKD. Epigenetic repression of HNF1B, induced by renal tubular stress, drives CKD progression.: Inactivation of Hnf1b in quiescent renal tubular epithelial cells induces rapid dedifferentiation and abrupt cell cycle reentry, leading to replication stress, cell death, and ultimately, severe chronic kidney disease (CKD). To capture the earliest molecular events preceding tissue damage, we combined ChIP-seq and transcriptomic analyses in kidneys from Hnf1b mutant mice 2 days after gene inactivation, before the appearance of histological lesions. This analysis identified a prelesional HNF1B transcriptional signature, which was markedly reduced in multiple mouse models of CKD as well as in human CKD even before lesion development. Analysis of a cohort of ~900 patients revealed that reduced expression of this signature strongly correlates with renal function decline. CKD-associated stresses, including albuminuria and interferon-γ, diminished HNF1B transcriptional activity in renal tubular cells. Together, these findings uncover a feed-forward pathogenic loop in which HNF1B deficiency promotes CKD progression, whereas CKD-associated stresses further suppress HNF1B activity through epigenetic mechanisms. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of Science is the property of American Association for the Advancement of Science and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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