Aristolochic acid induces chronic kidney disease in ace knockout mice

Abstract

Background: Aristolochic acid I (AAI) is an extract from Chinese herbs that causes progressive interstitial nephritis. The aim of this research is to know whether chymases play the crucial role in AAI-induced nephropathy. Methods: The mice were treated with AAI via intraperitoneal injection and the accumulated AAI dosages are 30 mg/kg of body weight for two, four, six, and eight weeks. The animals were sacrificed after another two or four weeks for nephropathy development. Collection of blood, urine, and kidney samples for the further biochemical analysis, hematoxylin–eosin (H and E) and Masson's trichrome stained to detected pathologic, and MMP2 and MMP9 activity assays. Results: After the treatment of AAI, of the mice, their body weights were decreased (P < 0.01), and concentration of creatinine and blood urea nitrogen (BUN) in serum (P < 0.01) and urine collection were increased (P < 0.01). In the renal tissue sections, high amount of inflammatory cells were found by H and E stain, and increased fibrosis in renal interstitial tissue were observed by Masson's trichrome stain. In mice kidney tissue, significantly increased chymase activity after treatment of AAI was found (P < 0.01), but ACE activity did not show significant changes. In ACE KO mice, increased MMP2 and decreased MMP9 activity were found in the AAI-treated mice compared with AAI-untreated control (P < 0.01). Conclusions: Moreover, it was also observed that the deficiency of ACE would accelerate the disease development of AAI-induced nephropathy. These results may help to know more information about the role of AAI-induced chronic kidney disease and can be applied in developing new drug targets for nephropathy.

Keywords

• aristolochic acid i
• chronic kidney disease
• chymases
• peptidyl-dipeptidase a
• renal insufficiency