Silencing of Hypoxia-Inducible Factor-1α Gene Attenuated Angiotensin II–Induced Renal Injury in Sprague-Dawley Rats
Although it has been shown that upregulation of hypoxia-inducible factor (HIF)-1α is protective in acute ischemic renal injury, long-term overactivation of HIF-1α is implicated to be injurious in chronic kidney diseases. Angiotensin II (Ang II) is a well-known pathogenic factor producing chronic renal injury and has also been shown to increase HIF-1α. However, the contribution of HIF-1α to Ang II–induced renal injury has not been evidenced. The present study tested the hypothesis that HIF-1α mediates Ang II–induced renal injury in Sprague-Dawley rats. Chronic renal injury was induced by Ang II infusion (200 ng/kg per minute) for 2 weeks in uninephrectomized rats. Transfection of vectors expressing HIF-1α small hairpin RNA into the kidneys knocked down HIF-1α gene expression by 70%, blocked Ang II–induced HIF-1α activation, and significantly attenuated Ang II–induced albuminuria, which was accompanied by inhibition of Ang II–induced vascular endothelial growth factor, a known glomerular permeability factor, in glomeruli. HIF-1α small hairpin RNA also significantly improved the glomerular morphological damage induced by Ang II. Furthermore, HIF-1α small hairpin RNA blocked Ang II–induced upregulation of collagen and α-smooth muscle actin in tubulointerstitial region. There was no difference in creatinine clearance and Ang II–induced increase in blood pressure. HIF-1α small hairpin RNA had no effect on Ang II–induced reduction in renal blood flow and hypoxia in the kidneys. These data suggested that overactivation of HIF-1α–mediated gene regulation in the kidney is a pathogenic pathway mediating Ang II–induced chronic renal injuries, and normalization of overactivated HIF-1α may be used as a treatment strategy for chronic kidney damages associated with excessive Ang II.
- Received June 6, 2011.
- Revision received June 23, 2011.
- Accepted July 29, 2011.
- © 2011 American Heart Association, Inc.