Probenecid prevents acute tubular necrosis in a mouse model of aristolochic acid nephropathy

Abstract

Experimental aristolochic acid nephropathy is characterized by early tubulointerstitial injury followed by fibrosis, reproducing chronic lesions seen in humans. In vitro, probenecid inhibits aristolochic acid entry through organic anion transporters, reduces specific aristolochic acid-DNA adduct formation, and preserves cellular viability. To test this in vivo, we used a mouse model of aristolochic acid nephropathy displaying severe tubulointerstitial injuries consisting of proximal tubular epithelial cell necrosis associated to transient acute kidney injury followed by mononuclear cell infiltration, tubular atrophy, and interstitial fibrosis. Treatment with probenecid prevented increased plasma creatinine and tubulointerstitial injuries, and reduced both the extent and the severity of ultrastructural lesions induced by aristolochic acid, such as the loss of brush border, mitochondrial edema, and the disappearance of mitochondrial crests. Further, the number of proliferating cell nuclear antigen-positive cells and total aristolochic acid-DNA adducts were significantly reduced in mice receiving aristolochic acid plus probenecid compared with mice treated with aristolochic acid alone. Thus, we establish the nephroprotective effect of probenecid, an inhibitor of organic acid transporters, in vivo toward acute proximal tubular epithelial cell toxicity in a mouse model of aristolochic acid nephropathy.

Impact of genetic modulation of SULT1A enzymes on DNA adduct formation by aristolochic acids and 3-nitrobenzanthrone

“…Mouse models and cells derived from mice are often used to study experimental AAN and mechanisms related to AA carcinogenesis (Arlt et al 2011; Baudoux et al 2012; Krais et al 2015; Nik-Zainal et al 2015; Odell et al 2013; Wang et al 2012). Thus, it is also important to understand the role of murine Sults on AA bioactivation.…”

An Integrated View of Aristolochic Acid Nephropathy: Update of the Literature

“…Only a few in vivo studies addressing AA transport in PTEC have been described in the literature [95,96,97]. In AA-treated mice, probenecid treatment has been found to decrease the renal distribution and the urinary excretion of AAI [95] but also to reduce tubular necrosis, lymphocytic infiltrate, tubular atrophy as well as fibrosis by blocking AA entry into PTEC as attested by the reduction of DNA-adducts formation [97]. In addition, Oat1 and Oat3 KO mice also displayed protection from experimental AA-induced nephropathy through reduction of AAI accumulation in PTEC [95].…”

“…Finally, several other transport mechanisms than OAT have also been proposed regarding AA uptake into PTEC [77,95,97]. Since a time- and dose-dependent accumulation of AAI and AAII has been observed in control CHO-K1 transfected cells (that do not express OAT), it has been proposed that these compounds could enter the cells through simple diffusion [77].…”

Bioinformatics facilitating the use of microarrays to delineate potential miRNA biomarkers in aristolochic acid nephropathy

“…Patients taking aristolochic acid have a high risk (~50%) of upper urothelial tract carcinoma as well as bladder urothelial carcinoma within a few years; such cases have occurred in Europe and Asia [2, 3]. The predominant lesion of AAN is characterised by tubulointerstitial fibrosis, with tubular atrophy atrophy/loss and global glomerular sclerosis [2, 4, 5]. Apoptosis, epithelial-mesenchymal transition (EMT), and fibrosis are the main pathologic manifestations of the development of AAN.…”