title: Silencing of hypoxia-inducible factor-1α gene attenuated angiotensin II-induced renal injury in Sprague-Dawley rats.
abstract: 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.
authors: Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, VA 23298, USA.
authors: Qing
authors: Q
authors: Zhu
authors: Zhengchao
authors: Z
authors: Wang
authors: Min
authors: M
authors: Xia
authors: Pin-Lan
authors: PL
authors: Li
authors: Benjamin W
authors: BW
authors: Van Tassell
authors: Antonio
authors: A
authors: Abbate
authors: Romesh
authors: R
authors: Dhaduk
authors: Ningjun
authors: N
authors: Li
mesh_terms: D000419:Albuminuria / Q000139:chemically induced / Q000517:prevention & control / Q000652:urine; D000804:Angiotensin II / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D003404:Creatinine / Q000652:urine; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects / Q000502:physiology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D003404:Creatinine