Poster 23 - Yuma Iwamura, Growth and Metabolism

Summary

Diabetic kidney disease (DKD) is the major cause of mortality in patients with diabetes. Hypoxia in renal tubules is the driving force for tubular atrophy and interstitial fibrosis, which can further reinforce glomerular pathology during the development of diabetic nephropathy. Hypoxiainducible factor-1 (HIF-1) is the major regulator of adaptive responses to hypoxia. However, HIF-1 signaling is inhibited in diabetic kidney, contributing to the progression of DKD. The destabilization of HIF-1 in diabetes is mainly through the von Hippel-Lindau protein (VHL) - mediated degradation of HIF-1a. However, the role of tubular VHL in DKD is still not clear.
In this study, we first evaluated the effects of VHL gene silencing in mouse tubular epithelial mIMCD3 cells. VHL gene silencing increased the expression of HIF-1a protein and reduced ROS levels in cells that were exposed to high glucose levels in hypoxia. 
We then generated tubule - specific VHL knockout (VHL-KO) mice. Diabetes was induced in the mice with streptozotocin i.p. injections. Kidney pathology and renal function were analyzed 6 weeks after the induction of diabetes. Tubule-specific VHL ablation increased expression of HIF-1a and HIF-1 target genes and reduced ROS levels in the kidneys from diabetic mice. This is accompanied by reduced kidney injury demonstrated by decreased expression of Kidney Injury Marker–1 (KIM-1) and reduced TUNELpositive apoptotic cells. Albuminuria was significantly ameliorated in diabetic VHL-KO mice, indicating that the development of DKD was inhibited by tubule-specific VHL gene ablation.

Conclusion: Tubule-specific VHL gene ablation can

• Increase HIF-1a and its target gene expression
• Reduce ROS levels
• Ameliorate renal injury and renal function

Tubular VHL is a potential therapeutic target for diabetic kidney disease.