title: Transient hypoxia-inducible factor activation in rat renal ablation and reduced fibrosis with L-mimosine.
abstract: OBJECTIVE
  Hypoxia-inducible factor (HIF) activity during the course of chronic kidney disease (CKD) development is poorly defined, and the effect of HIF activation on CKD is still controversial. The purpose of the present study was to characterize HIF expression during the course of CKD development, and to investigate the effect of HIF activation on CKD by using prolyl hydroxylase (PHD) inhibitor L-mimosine.
  
  
  METHODS
  Rats with remnant kidneys (RK) were killed at week 1, 2, 4, 6, 8, 12 after subtotal nephrectomy. An additional group of RK rats was treated with L-mimosine to study the effect of HIF-α activation.
  
  
  RESULTS
  Tubulointerstitial hypoxia in the remnant kidney began at week 1 and continued, albeit attenuated, until week 12, the last time point examined. The nuclear expression of HIF-1α and HIF-2α, as well as typical HIF target genes VEGF (vascular endothelial growth factor), HO-1 (heme oxygenase-1), GLUT-1 (glucose transporter-1) and EPO (erythropoietin), were all upregulated in the early stage of RK when renal function was stable, and returned to the basal level later, accompanied by impaired renal function and interstitial fibrosis. L-mimosine administered from week 5 to week 12 led to accumulation of HIF-1α and HIF-2α proteins, increased expression of VEGF, HO-1 and GLUT-1, and improved renal function. Furthermore, fibrosis markers α-smooth muscle actin (α-SMA) and Collagen III, as well as peritubular capillary rarefaction index, were all significantly decreased after L-mimosine treatment.
  
  
  CONCLUSIONS
  There was a transient HIF-α activation in the remnant kidney of rats at the early stage following subtotal nephrectomy. L-mimosine administered in later stages re-activated HIF-α and reduced tubulointerstitial fibrosis.
authors.affiliation: Department 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: Xiaoqiang
authors.initials: X
authors.lastname: Ding
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: Yihong
authors.initials: Y
authors.lastname: Zhong
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D004195:Disease Models, Animal; D004921:Erythropoietin / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000503:physiopathology; D007677:Kidney Function Tests; D008898:Mimosine / Q000378:metabolism / Q000494:pharmacology*; D009392:Nephrectomy / Q000009:adverse effects / Q000379:methods; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors*; D051381:Rats; D051437:Renal Insufficiency / Q000150:complications / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D008898:Mimosine; D011393:Procollagen-Proline Dioxygenase; D051547:Heme Oxygenase-1