Kidney Week

Abstract: SA-PO119

VHL Deletion in Renal Proximal Tubules of Mice Ameliorates Hallmarks of Diabetic Nephropathy

Session Information

• Diabetic Kidney Disease: Basic - III
  October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Bötttner, Martina, University of Kiel, Kiel, Germany

Martina Bötttner,

• Dahlke, Eileen, CAU Kiel, Kiel, Germany

Eileen Dahlke,

• Theilig, Franziska, Christian-Albrechts University zu Kiel, Kiel, Germany

Franziska Theilig,

Background

Diabetic nephropathy is the leading cause of end-stage renal disease and frequently affects patients with type 2 diabetes mellitus. Glomerular hyperfiltration and phenotypic changes in proximal tubule epithelial cells (PTECs) are the initial signs of diabetic nephropathy. Systemic activation of hypoxia-inducible factors (HIFs) was shown to prevent diabetes-induced alterations in kidney oxygen metabolism.

Methods

To analyze in detail whether renal tubular HIF activation is sufficient to prevent functional and morphological alteration of diabetic nephropathy, SGLT2^Cre/VHL^flox mice were generated and diabetes mellitus was induced by streptozotocin application.

Results

FITC-inulin clearance analysis revealed a strong increase in diabetic VHL^flox control mice which was abrogated in diabetic SGLT2^Cre/VHL^flox mice showing similar values as the non-diabetic control mice. Blood glucose concentration and urinary volume excretion were significantly increased in diabetic mice without significant differences between genotypes. However, osmotically-induced hyponatremia was only observed in diabetic VHL^flox mice whereas diabetic SGLT2^Cre/VHL^flox had values similar to non-diabetic controls. Urinary electrolyte, glucose and phosphate excretion was increased in diabetic mice and more pronounced in diabetic SGLT2^Cre/VHL^flox compared to diabetic VHL^flox mice.

Conclusion

In summary, our study reveals that induction of proximal tubular HIF are able to prevent diabetes induced glomerular hyperfiltration. Additionally, osmotically-induced hyponatremia was also prevented upon HIF activation most probably through reduced proximal tubular glucose reabsorption and thereby leading to its increased urinary excretion.

Funding

• Private Foundation Support