Hypoxia-inducible factor-1α contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells.
To examine whether hypoxia-inducible factor (HIF)-1α mediates the profibrotic effects of angiotensin II, we treated cultured renal medullary interstitial cells with angiotensin II and found that it increased HIF-1α levels. This was accompanied by a significant upregulation of collagen I/III, the tissue inhibitor of metalloproteinase-1, elevation of the proliferation marker proliferating cell nuclear antigen, and a transdifferentiation marker vimentin. All these effects of angiotensin II were completely blocked by siRNA for HIF-1α but not HIF-2α. Overexpression of a prolyl-hydroxylase domain-containing protein 2 (PHD2) transgene, the predominant renal HIF prolyl-hydroxylase, attenuated the effects of angiotensin II and its gene silencing enhanced the effects of angiotensin II. Removal of hydrogen peroxide eliminated angiotensin II-induced profibrotic effects. A 2-week infusion of rats with angiotensin II increased the expression of HIF-1α and α-smooth muscle actin, another marker of transdifferentiation, in renal medullary interstitial cells in vivo. Thus, our study suggests that HIF-1α mediates angiotensin II-induced profibrotic effects through activation of cell transdifferentiation. We propose that redox regulation of prolyl-PHD2 plays a critical role in angiotensin II-induced activation of HIF-1α in renal cells.
Wang
Zhengchao
Z
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
Tang
Lin
L
Zhu
Qing
Q
Yi
Fan
F
Zhang
Fan
F
Li
Pin-Lan
PL
Li
Ningjun
N
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000008:administration & dosage / Q000378:metabolism*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D054338:Cell Transdifferentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005355:Fibrosis; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007679:Kidney Medulla / Q000378:metabolism* / Q000473:pathology; D008297:Male; D011393:Procollagen-Proline Dioxygenase / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D014746:Vimentin / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D000199:Actins; D000804:Angiotensin II; D051792:Basic Helix-Loop-Helix Proteins; D024042:Collagen Type I; D024061:Collagen Type III; D006861:Hydrogen Peroxide; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D011393:Procollagen-Proline Dioxygenase; D018809:Proliferating Cell Nuclear Antigen; D019715:Tissue Inhibitor of Metalloproteinase-1; D014746:Vimentin; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat; C498862:Acta2 protein, rat; C580731:Egln1 protein, rat