Role of peritubular capillary loss and hypoxia in progressive tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy.
OBJECTIVE
To investigate the effects of peritubular capillary (PTC) loss and hypoxia on the progression of tubulointerstitial fibrosis in a rat model of aristolochic acid nephropathy (AAN).


METHODS
Female Wistar rats received Caulis aristolochiae manshuriensis (CAM) decoction by gavage for 8 weeks, and were sacrificed at 8, 12 and 16 weeks, respectively, after administration. Blood urea nitrogen (BUN), serum creatinine (Scr) and urinary protein were monitored prior to sacrifice. PTC loss and tubulointerstitial hypoxia were assessed by CD34 immunostaining and hypoxia-inducible factor-alpha subunit 1 (HIF-1alpha) expression, respectively. Myofibroblasts were assessed by alpha-smooth muscle actin (alpha-SMA) expression. The expression of angiogenic factor was assessed by vascular endothelial growth factor (VEGF).


RESULTS
AAN rats differed from controls by increased BUN, Scr and 24-hour urinary protein excretion rates. There was a progressive loss of PTCs in the AAN model, which was associated with the decreased expression of VEGF. A significant increase in nuclear localization of HIF-1alpha was seen 16 weeks after treatment with CAM decoction in the context of severe tubulointerstitial damage. Multifocal tubulointerstitial fibrosis was seen in AAN rats at weeks 12 and 16, predominantly in the area of the outer stripe and outer medulla. No significant pathologic changes were found in control rats.


CONCLUSIONS
Following the reduction of PTCs density and up-regulation of HIF-1alpha, the tubulointerstitial fibrosis area increased. Ischemia and hypoxia are the important causes of severe tubulointerstitial fibrosis in AAN rats.
Sun
Dong
D
Department of Nephrology, First Affiliated Hospital of China Medical University, Shenyang City, Liaoning Province, PR China.
Feng
Jiangmin
J
Dai
Chun
C
Sun
Li
L
Jin
Tao
T
Ma
Jianfei
J
Wang
Lining
L
D000818:Animals; D034341:Aristolochic Acids / Q000009:adverse effects*; D002196:Capillaries / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D018450:Disease Progression; D004365:Drugs, Chinese Herbal / Q000009:adverse effects*; D005260:Female; D005355:Fibrosis; D000860:Hypoxia / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D007684:Kidney Tubules / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D051381:Rats; D017208:Rats, Wistar
D034341:Aristolochic Acids; D004365:Drugs, Chinese Herbal