Aristolochic Acids Induce Chronic Renal Failure with Interstitial Fibrosis in Salt-Depleted Rats

Abstract

ABSTRACT. Chinese-herb nephropathy (CHN) is a rapidly progressive renal fibrosis associated with the intake of a Chinese herb (Aristolochia fangchi) containing nephrotoxic and carcinogenic aristolochic acids (AA). This study attempted to reproduce the main features of human CHN (renal failure, tubular atrophy, and interstitial fibrosis) in a rat model similar to that of cyclosporin-induced nephropathy. Salt-depleted male Wistar rats received daily subcutaneous injections of either 1 mg/kg body wt AA (low-dose AA group), 10 mg/kg body wt AA (high-dose AA group), or vehicle (control group) for 35 d. On days 10 and 35, assessment of renal function, measurements of urinary excretion of glucose, protein, and leucine aminopeptidase, and histologic analyses were performed (six rats euthanized/group). High-dose AA induced glucosuria, proteinuria, and elevated serum creatinine levels and reduced leucine aminopeptidase enzymuria on days 10 and 35, whereas low-dose AA had no significant effect. Tubular necrosis associated with lymphocytic infiltrates (day 10) and tubular atrophy surrounded by interstitial fibrosis (day 35) were the histologic findings for the high-dose AA-treated rats. In both AA groups, urothelial dysplasia was also observed, as well as fibrohistiocytic sarcoma at the injection site. A short-term model of AA-induced renal fibrosis was established in salt-depleted Wistar rats. These results support the role of AA in human CHN and provide a useful model for examination of the pathophysiologic pathways of renal fibrosis.

Treatment of Lupus Nephritis from Iranian Traditional Medicine and Modern Medicine Points of View: A Comparative Study

“…(2) Aristolochia species. Aristolochia species roots, known as zaravand in ITM [ 96 ], include aristolochic acid (AA) [ 74 ] that causes chronic interstitial renal fibrosis [ 72 ], proximal tubular toxicity [ 73 ], aristolochic acid nephropathy (AAN) [ 74 , 75 ], severe hypocellular interstitial fibrosis, urothelial dysplasia [ 76 ], renal failure with interstitial fibrosis [ 77 ], Balkan endemic nephropathy (BEN) [ 78 , 79 ], and Fanconi's syndrome [ 73 , 80 – 82 ]. It seems that tubular compartment is the main target of AA and AA exerts apoptotic effects via activating mitochondrial permeability and activating caspase-3 [ 100 ].…”

The application of mass spectrometry imaging in traditional Chinese medicine: a review

“…MSI has also been employed to evaluate the toxicological mechanisms of a drug. Aristolochic acid (AAI) is a toxic natural component existing in a number of TCM related species, the administration of which would induce nephrotoxicity [ 148 ]. Kidney sections of rats treated with AAI were analyzed using AFADESI-MSI.…”

Tongluo Yishen Decoction Ameliorates Renal Fibrosis via Regulating Mitochondrial Dysfunction Induced by Oxidative Stress in Unilateral Ureteral Obstruction Rats

“…These sections were then stained with hematoxylin and eosin (H&E) and Masson's trichrome. The kidney injury score was determined based on tubular atrophy and degeneration, renal papillary necrosis, interstitial inflammation, and fibrous hyperplasia as previously reported (Debelle et al, 2002).…”