title: The balance of beneficial and deleterious effects of hypoxia-inducible factor activation by prolyl hydroxylase inhibitor in rat remnant kidney depends on the timing of administration.
abstract: BACKGROUND
  Chronic hypoxia in the kidney has been suggested as a final common pathway in the progression of chronic kidney disease (CKD) leading to eventual kidney failure. Hypoxia-inducible factor (HIF) activation might offer a promising approach to the protection of hypoxic tissues, but the effect of HIF activation on CKD is still controversial. In this study, we investigated whether HIF activation had a beneficial or deleterious effect on CKD in the rat remnant kidney (RK) model.
  
  
  METHODS
  One week after a subtotal nephrectomy, rats were randomized and each received special administration of prolyl hydroxylases (PHD) inhibitor L-mimosine (L-Mim) as follows: in the early long-time L-Mim treatment group they were administered L-Mim at Weeks 2-12; in the advanced medium-term L-Mim treatment group they were administered L-Mim at Weeks 4-12 and in the end-stage L-Mim treatment group they were administered L-Mim at Weeks 8-12.
  
  
  RESULTS
  Compared with the control group, renal dysfunction and increased collagen III deposition, α-smooth muscle actin expression and ED-1-positive macrophage infiltration in tubulointerstitium were exacerbated by early long-term L-Mim treatment and improved by advanced medium-term L-Mim treatment. End-stage L-Mim treatment had no effect on RK rats. Furthermore, early long-term L-Mim treatment activated HIF-1α, connective tissue growth factor (CTGF) and phospho-Smad3 prominently throughout the time course and activated HIF-2α, vascular endothelial growth factor (VEGF) and erythropoietin (EPO) slightly at the end stage, while advanced medium-term L-Mim treatment activated HIF-2α, VEGF and EPO significantly and had no effect on HIF-1α, CTGF and phospho-Smad3.
  
  
  CONCLUSIONS
  HIF-α activation by PHD inhibitor L-Mim has dual roles in the development of CKD in the rat RK model depending on the timing of the administration and possibly the activated isoform of HIF-α.
authors.affiliation: Division of Nephrology, Zhongshan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Xiaofang
authors.initials: X
authors.lastname: Yu
authors.forename: Yi
authors.initials: Y
authors.lastname: Fang
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.forename: Jiaming
authors.initials: J
authors.lastname: Zhu
authors.forename: Jianzhou
authors.initials: J
authors.lastname: Zou
authors.forename: Xunhui
authors.initials: X
authors.lastname: Xu
authors.forename: Suhua
authors.initials: S
authors.lastname: Jiang
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Ding
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D049308:Dioxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018450:Disease Progression; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage*; D005355:Fibrosis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology; D008297:Male; D008898:Mimosine / Q000008:administration & dosage*; D009392:Nephrectomy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D000199:Actins; D051792:Basic Helix-Loop-Helix Proteins; D024061:Collagen Type III; D049308:Dioxygenases; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008898:Mimosine; D012333:RNA, Messenger; D000099162:Endothelial PAS Domain-Containing Protein 1; C497444:Hif1a protein, rat; C498862:Acta2 protein, rat; C552717:HIF prolyl hydroxylase, rat