Role of mitochondrial permeability transition in human renal tubular epithelial cell death induced by aristolochic acid

Aristolochic acid (AA), a natural nephrotoxin and carcinogen, can induce a progressive tubulointerstitial nephropathy. However, the mechanism by which AA causes renal injury remains largely unknown. Here we reported that the mitochondrial permeability transition (MPT) plays all important role in the renal injury induced by aristolochic acid I (AA1). We found that in the presence of Ca2+, AAI caused mitochondrial swelling. leakage of Ca2+ membrane depolarization, and release of cytochrome c in isolated kidney initochondria. These alterations were suppressed by cyclosporin A (CsA), an agent known to inhibit NIPT. Culture of HK-2 cell, a human renal tubular epithelial cell line for 24 h with AAI caused a decrease ill Cellular ATP, initochondrial membrane depolarization, cytochrome c release, and increase of caspase 3 activity. These toxic effects of AA1 were attenuated by CsA and bongkrekic acid (BA), another specific MPT inhibitor. Furthermore, AAI,really inhibited the activity of initochondrial adenine nucleotide translocator (ANT) in isolated rnitochondria. We suggested that ANT may mediate, at least in part, the AAI-induced NIPT. Taken together, these results suggested that MPT plays a critical role in the pathogenesis of HK-2 cell injury induced by AAI and implied that MPT might contribute to human nephrotoxicity of aristolochic acid. (c) 2007 Elsevier Inc. All rights reserved.