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Abstract: FR-PO511

The Effects of Hypoxia-Inducible Factors on Water Regulation in the Kidneys

Session Information

Category: Fluid, Electrolytes, and Acid-Base Disorders

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

Authors

  • Yang, Ching-Chun, National Taiwan University College of Medicine, Taipei, Taiwan
  • Huang, Kai-Ting, National Taiwan University College of Medicine, Taipei, Taiwan
  • Pan, Szu-Yu, National Taiwan University College of Medicine, Taipei, Taiwan
  • Lin, Shuei-Liong, National Taiwan University College of Medicine, Taipei, Taiwan
Background

Hypoxia-inducible factor (HIF) is one of important cellular responders when facing decreased oxygen tension or under hypoxia. HIF stabilization can improve anemia through erythropoietin production from kidneys; however, its overexpression could be seen in different cancer types, such as clear cell renal cell carcinoma. Previous studies have shown wide-spread HIF-1a-dependent hyperplastic, inflammatory and fibrotic lesions in the kidney of mice with von Hippel-Lindau gene (Vhlh) deletion in Hoxb7-expressing renal collecting duct (CD) epithelia. Interestingly, Vhlh deletion in Ksp1.3-expressing renal tubular epithelia has also been reported to cause HIF-1a dependent diuresis in mice.

Methods

Tg(Hoxb7-cre);VhlhF/F (Vhlh KO), Tg(Hoxb7-Cre);VhlhF/F;Hif1aF/F (Vhlh;Hif1a DKO), and Tg(Hoxb7-Cre);VhlhF/F;Hif2aF/F (Vhlh;Hif2a DKO) mice were bred to study the effect of HIF stabilization in Hoxb7-expressing renal CD epithelia. Littermate without Hoxb7-cre transgene was used as the control to compare body weight, blood and urine biochemistry, gene/protein expression and histology in kidney.

Results

Compared to littermate control, Vhlh KO mice exhibited higher 24-hour urine volume and lower urine osmolality which could be partially ameliorated by water deprivation. Water deprivation-induced, vasopressin-dependent urine concentration was not different between Vhlh KO mice and littermate control. Vhlh KO mice exhibited higher food intake and solute diuresis, but decreased body weight. Food restriction led to similar excretion of urine solutes, but Vhlh KO mice consistently exhibited higher urine volume and lower urine osmolality than littermate control. Vhlh;Hif2a DKO mice exhibited higher urine volume and lower urine osmolality, but no more solute diuresis. Vhlh;Hif1a DKO mice did not exhibit abnormality in urine volume and osmolality. Histologically, Vhlh KO mice exhibited substantial tubulointerstitial injury.

Conclusion

Vhlh KO and hence HIF-1a/HIF-2a overexpression in renal CD epithelia led to HIF-1a-dependent decrease in renal concentrating ability. However, increase of solute diuresis was HIF-2a-dependent. Water deprivation-induced, vasopressin dependent urine concentration was not impaired in Vhlh KO mice. HIF-1a-dependent diuresis might be caused by destructed renal interstitium. But the mechanisms underlying HIF-2a-dependent solute diuresis need further study.

Funding

  • Government Support – Non-U.S.