[Influence of hypoxia caused by impairment of peritubular capillary on the progression of chronic aristolochic acid nephropathy].
OBJECTIVE
To investigate the manifestation of impairment of peritubular capillary (PTC) in chronic aristolochic acid nephropathy (CAAN) and the influence of hypoxia caused by PTC impairment on the progression of CAAN.


METHODS
Fifty-four Wistar rats were randomly divided into 2 groups: Group A (n = 30, perfused intragastrically with decoction of Caulis aristolochia manchuriensis for 8 weeks) and Group B (n = 24, perfused intragastrically with drinking water for 8 weeks). At weeks 8, 12, and 16 ten rats in Group A and 8 rats in Group B were killed. Specimens of blood and urine were collected before the killing of the rats to detect the blood urea nitrogen (BUN), serum creatinine (Scr), and urine protein. HE and Masson staining and microscopy were used to observe the pathology of the kidney. Immunohistochemistry and Western blotting were used to detect the expression of hypoxia-inducible factor-1alpha (HIF-1alpha), vascular endothelial growth factor (VEGF), and CD34. Correlation analysis was conducted to study the relationships among these indices.


RESULTS
Since week 8 BUN, Scr, and urine protein of Group A began to increase in comparison with Group B (all P < 0.05). Pathological changes of the kidney began to appear in Group A since week 8 with the decrease of PTC density. HIF-1alpha was not expressed in Group B, and in Group A HIF-1alpha expression began to increase since week 8 and became significantly higher than that of Group B since week 12. At week 16, the PTC density and VEGF-IOD of Group A were 8.10 +/- 2.28/0.13 mm(2) and (2.78 +/- 0.78) x 10(3) respectively, both significantly lower than those of Group B [(42.80 +/- 4.49)/0.13 mm(2) and (26.49 +/- 9.34) x 10(3) respectively, both P < 0.01], and the HIF-1alpha-IOD of Group A was (7.11 +/- 1.20) x 10(3), significantly higher than that of Group B [(0.44 +/- 0.10) x 10(3), P < 0.01]. CD34 was highly expressed in Group B, and the CD34 expression of Group A began to decrease since week 16. HIF-1alpha expression was positively correlated with Scr (r = -0.945, P < 0/01), and PTC density and VEGF expression were negatively correlated with Scr (r = -0.907, P < 0.01 and r = -0.690, P < 0.01). PTC density was negatively correlated with HIF-1alpha expression (r = -0.880, P < 0.01).


CONCLUSIONS
Severe hypoxia exists following PTC injury in CAAN. Hypoxia is correlated with the progression of CAAN.
Sun
Dong
D
Department of Nephrology, First Affiliated Hospital of China Medical University, Shenyang 110001, China.
Feng
Jiang-min
JM
Dai
Chun
C
Sun
Li
L
Jin
Tao
T
Wang
Zong-qian
ZQ
Ma
Jian-fei
JF
Wang
Li-ning
LN
D000818:Animals; D034341:Aristolochic Acids / Q000009:adverse effects; D002196:Capillaries / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051793:Hypoxia-Inducible Factor 1 / Q000096:biosynthesis; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D034341:Aristolochic Acids; D004268:DNA-Binding Proteins; D051793:Hypoxia-Inducible Factor 1; D042461:Vascular Endothelial Growth Factor A; C000228:aristolochic acid I