Abstract 31: Rt-pcr Profiling Reveals the Essential Role of Endothelial Hif-1a in Hypertensive Nephropathy
Chronic kidney disease is a devastating disease featured with kidney injury and renal fibrosis. Hypertension is a major cause of CKD. However, the specific factors underlying hypertensive nephropathy are unclear. Here we sought to identify specific factors that contribute to hypertensive CKD. Using RT-PCR array, we discovered that the hypoxia induced factor-1α (HIF-1α) mRNA was significantly increased in the kidneys of angiotensin II (AngII)-infused mice, a well-accepted animal model of hypertensive CKD. Immunohistochemsitry revealed that HIF-1α was significantly elevated in the endothelial cells of capillary lumen of glomeruli of AngII-infused mice. To determine the role of elevated endothelial HIF-1α in hypertensive CKD, we generated mice with specific endothelial HIF-1α deficiency by mating floxed HIF-1α mice with the V-Cadherine-Cre mice containing transgene expressing Cre recombinase only in the endothelial cells. First, we found that Ang II-induced-hypertension and proteinuria were significantly reduced in endothelial HIF-1α deficient mice compared to the control mice (150.88mmHg vs. 176.33mmHg systolic, p<0.05; 15.49ug/mg vs. 129.16ug/mg, p<0.001). Histological studies showed genetic deletion of endothelia HIF-1α attenuated glomerular damage and renal fibrosis in Ang II-infused mice. Mechanistically, we further revealed that genetic deficiency in endothelial HIF-1α significantly reduced levels of endothelin-1 (ET-1), a potent vasoconstrictor, in both kidneys and circulation of Ang II-infused mice. Intriguingly, using primary mouse kidney organ cultures, we provide genetic evidence that Ang II-mediated ET-1 production was significantly reduced in the cultured kidneys from endothelial HIF-1α-deficient mice, indicating that Ang II is a hypoxia-independent factor capable of inducing HIF-1α production and contributing to ET-1 elevation in the mouse kidneys. Lastly, we revealed that both HIF-1α and ET-1 levels were significantly elevated in the kidneys of CKD patients compared to normal individuals and further elevated in hypertensive CKD patients. Overall, both the mouse and human studies provide strong evidence that elevated endothelial HIF-1α-mediated excess ET-1 is a prominent driver of hypertensive CKD.
- © 2013 by American Heart Association, Inc.