Role of Peritubular Capillary Loss and Hypoxia in Progressive Tubulointerstitial Fibrosis in a Rat Model of Aristolochic Acid Nephropathy

• Published in: American journal of nephrology Vol. 26; no. 4; pp. 363 - 371
• Main Authors: Sun, Dong, Feng, Jiangmin, Dai, Chun, Sun, Li, Jin, Tao, Ma, Jianfei, Wang, Lining
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Karger 01.01.2006; S. Karger AG
• Subjects: Animals; Aristolochic Acids - adverse effects; Biological and medical sciences; Capillaries - drug effects; Capillaries - pathology; Capillaries - physiopathology; Disease Models, Animal; Disease Progression; Drugs, Chinese Herbal - adverse effects; Female; Fibrosis; Hypoxia - chemically induced; Hypoxia - pathology; Hypoxia - physiopathology; Kidney Tubules - blood supply; Kidney Tubules - drug effects; Kidney Tubules - pathology; Medical sciences; Nephritis, Interstitial - chemically induced; Nephritis, Interstitial - pathology; Nephritis, Interstitial - physiopathology; Nephrology. Urinary tract diseases; Original Report: Laboratory Investigation; Rats; Rats, Wistar; Tubulointerstitial fibrosis; Aristolochic acid nephropathy; Peritubular capillary loss; Kidney disease; Animal model; Oxygen; Nephrology; Urinary system disease; Rat; Rodentia; Peritubular capillary loss . Aristolochic acid nephropathy; Urology; Progressive; Vertebrata; Mammalia; Nephropathy; Acids; Fibrosis; Hypoxia
• ISSN: 0250-8095; 1421-9670
• DOI: 10.1159/000094778

Background/Aims: 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-α subunit 1 (HIF-1α) expression, respectively. Myofibroblasts were assessed by α-smooth muscle actin (α-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-1α 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. Conclusion: Following the reduction of PTCs density and up-regulation of HIF-1α, the tubulointerstitial fibrosis area increased. Ischemia and hypoxia are the important causes of severe tubulointerstitial fibrosis in AAN rats.