Western diet exacerbates aristolochic acid-induced nephropathy in mice

Abstract

Aristolochic acid (AA) ingestion causes Balkan nephropathy, characterized by tubular injury and progression to chronic kidney disease (CKD). AA is taken up by proximal tubule cells via organic anion transport (OAT3) and induces p53-mediated DNA damage, but little is known about modulating factors. The Western diet (WD) is rich in saturated fats, sugars, and salt and contributes to the development of metabolic disorders such as obesity and diabetes, but also to the progression of CKD. The aim of this study was to elucidate the impact of WD on AA-induced kidney injury. 5-week-old male C57BL6 mice were fed with WD or normal chow (NC) for 8 weeks, followed by administration of AA every 3 days at a dose of 3 mg/kg for 3 weeks. Samples were collected after a 3-week recovery period (n=4/group for vehicle; n=7-8/group for AA). The AA-induced increase in plasma creatinine and the reduction of hematocrit were significantly greater in WD vs NC. This was associated with increased kidney gene expression in WD vs NC of markers of DNA damage ( p53), injury ( Kim1 and Ngal), and inflammation ( Tnfa). The WD group had a greater body weight and, therefore, received a higher total dose of AA (0.73 and 0.6 mg), which may have worsened kidney injury. Therefore, in a second series, the same total dose of AA (0.9 mg) was administered to WD and NC groups. WD similarly increased the AA-induced fall in hematocrit and rise in plasma creatinine and renal p53, Kim1, Ngal, and Tnfa mRNA expression compared to the NC group. Moreover, WD increased renal mRNA expression of Oat3. These findings suggest that WD increases the susceptibility to AA nephrotoxicity, possibly through upregulation of OAT3. This model may be useful for studying the mechanistic impact of Western diet on the development and progression of CKD caused by nephrotoxic agents. Supported by National Institutes of Health (NIH) Grants RF1AG061296 (PM, VV), R01DK132690 (VV), and P30 DK079337 (VV), the Department of Veterans Affairs, and a fellowship of the Manpei Suzuki Diabetes Foundation (YO). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.