Introduction: Hypertension and chronic kidney disease (CKD) drive each other and they are 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 both hypertension and CKD. We and others have recently showed that persistently elevated HIF-1a in particular in endothelial cells contributes to hypertensive models induced by angiotension II, a potent vasoconstrictor. However, the role of endothelial HIF-1α in hypertension and CKD remains unidentified.
Hypothesis: To determine the general significance of persistently elevated endothelial HIF-1 in hypertension and CKD, we used LIGHT, a new family member of TNF-α super family-infused hypertensive CKD mouse model.
Methods: Six to twelve VE-cadherin cre+ mice and Hif-1αf/fVE-cadherin cre+ mice for each group were infused with LIGHT by minipump (4ng/day) and PBS as controls.. We collected urine for proteinuria analysis and measured blood pressure on day 0, 3, 7, 10, 14 post infusion of LIGHT. On day 14, mice were sacrificed.
Results: We found that LIGHT infusion induced persistently elevated HIF-1α protein levels in endothelial cells of capillary lumen of glomeruli in the control HIF-1αf/f mice. Additionally, we revealed that LIGHT-induced hypertension, proteinuria, and renal fibrosis. In contrast, genetic deletion of endothelial specific HIF-1α attenuated LIGHT-induced hypertension, proteinuria and renal fibrosis. Mechanistically, we identified that endothelial HIF-1α gene expression was induced by LIGHT in a NF-κB-dependent manner. These studies led us to further discover that the 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 hypertension and CKD.
Conclusions: Our findings highlight early diagnostic opportunities and therapeutic approaches for hypertension and CKD.