Kidney Week

Abstract: TH-PO0034

Hypoxia-Inducible Factor-1 Overexpression Triggers Water Diuresis by Reducing Aquaporin-2 Expression

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  October 22, 2026 | Location: Exhibit Hall A, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Pan, Szu-Yu, National Taiwan University Hospital, Taipei City, Taiwan

Szu-Yu Pan, MD, PhD

• Yang, Ching-Chun, National Taiwan University College of Medicine, Taipei City, Taiwan

Ching-Chun Yang, MS, MSc

• Yu, Ming-Jiun, National Taiwan University College of Medicine, Taipei City, Taiwan

Ming-Jiun Yu, PhD

• Lin, Shuei-Liong, National Taiwan University Hospital, Taipei City, Taiwan

Shuei-Liong Lin, MD, PhD

Background

Hypoxia-inducible factor-1 (HIF-1) overexpression in mouse renal tubules has been reported to cause polyuria. We aimed to study the underlying mechanisms.

Methods

Tg(Hoxb7-Cre);Vhl^F/F, Tg(Hoxb7-Cre);Vhl^F/F;Epas1^F/F, and Tg(Hoxb7-Cre);Vhl^F/F;Hif1a^F/F mice were generated to study the effects of HIF-1 or HIF-2 overexpression in renal collecting ducts. Mouse kidney cortical collecting duct principal cells (mpkCCD) with Vhl knockdown were subjected to RNA sequencing to gain mechanistic insights.

Results

Polyuria was observed in Tg(Hoxb7-Cre);Vhl^F/F and Tg(Hoxb7-Cre);Vhl^F/F;Epas1^F/F mice, but was absent in Tg(Hoxb7-Cre);Vhl^F/F;Hif1a^F/F mice, identifying HIF-1 as the primary driver. The Tg(Hoxb7-Cre);Vhl^F/F;Epas1^F/F phenotype—characterized by water diuresis resistant to water restriction and exogenous vasopressin—aligns with arginine vasopressin resistance (AVP-R). This condition correlates with significant downregulation of medullary aquaporin-2 mRNA and protein (Figure), without structural vascular changes. Consistent with these findings, Vhl knockdown in mpkCCD cells reduced aquaporin-2 expression independently of vasopressin. Transcriptomic analysis via bulk RNA sequencing indicated that Vhl deficiency induces hypoxia responses, promotes a keratinocyte-like cell identity switch in the collecting duct, and downregulates essential water homeostasis genes.

Conclusion

HIF-1 overexpression in the collecting duct leads to decreased aquaporin-2 transcription and a reduced ability to regulate water homeostasis, in association with a lineage infidelity toward a keratinocyte identity.