Abstract: SA-PO389

Essential Role of Endothelial HIF-1a in Light-Induced Hypertensive CKD

Session Information

Category: Chronic Kidney Disease (Non-Dialysis)

  • 301 CKD: Risk Factors for Incidence and Progression

Author

  • Luo, Renna, The First Affiliated Hospital of Dalian Medical University, Dalian, China
Background

Hypertensive chronic kidney disease (CKD) is one of the most prevalent medical conditions with high morbidity and mortality in the United States and worldwide. Emerging evidence indicates that increased inflammatory response is involved in hypertensive CKD. Supporting this notion, recent study show that infusion of cytokine to mice leads to chronic hypertension, such as LIGHT, a TNF-a superfamily member.To determine the general significance of persistently elevated endothelial HIF-1 in hypertensive CKD, we used LIGHT-infused hypertensive CKD mouse model.

Methods

We obtained VE-cadherin cre+ mice and Hif-1αf/fVE-cadherin cre+ mice from Dr. Holger Eltzchig’s laboratory in University of Colorado at Denver. Six to twelve mice for each group were infused with LIGHT by minipump(4ng/day). Control mice were infused with PBS. We collected urine and measured blood pressure at 0,3,7,10,14 day. After treatment for 14-days, mice were sacrificed.

Results

We first found that LIGHT infusion induced persistently elevated HIF-1a protein levels in endothelial cells of capillary lumen of glomeruli in the control HIF-1af/f mice. Then we identified that LIGHT-induced HIF-1a gene expression is crucial for prolonged accumulation of HIF-1a in the endothelial cells in hypertensive CKD by inducing a series of potent vasoactive components. As such, we further found that LIGHT-induced hypertension, proteinuria, decreased urinary osmotic pressure and renal fibrosis. Next, we found that endothelial HIF-1a gene expression was induced by LIGHT in a NF-kB-dependent manner. Finally, we discovered reciprocal positive transcriptional regulation of endothelial Hif-1α and Nf-κb genes is a key driving force for their persistent activation and disease progression. Overall, our findings revealed that the stimulation of HIF-1α in endothelial cells is detrimental to induce kidney injury, hypertension and disease progression.

Conclusion

Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertensive CKD.