Silencing of Hypoxia-Inducible Factor-1{alpha} 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.[1]References
- Silencing of Hypoxia-Inducible Factor-1{alpha} Gene Attenuated Angiotensin II-Induced Renal Injury in Sprague-Dawley Rats. Zhu, Q., Wang, Z., Xia, M., Li, P.L., Van Tassell, B.W., Abbate, A., Dhaduk, R., Li, N. Hypertension (2011) [Pubmed]
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