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 an important role in the renal injury induced by aristolochic acid I (AAI). We found that in the presence of Ca(2+), AAI caused mitochondrial swelling, leakage of Ca(2+), membrane depolarization, and release of cytochrome c in isolated kidney mitochondria. These alterations were suppressed by cyclosporin A (CsA), an agent known to inhibit MPT. Culture of HK-2 cell, a human renal tubular epithelial cell line for 24 h with AAI caused a decrease in cellular ATP, mitochondrial membrane depolarization, cytochrome c release, and increase of caspase 3 activity. These toxic effects of AAI were attenuated by CsA and bongkrekic acid (BA), another specific MPT inhibitor. Furthermore, AAI greatly inhibited the activity of mitochondrial adenine nucleotide translocator (ANT) in isolated mitochondria. We suggested that ANT may mediate, at least in part, the AAI-induced MPT. 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.
Qi
Xinming
X
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
Cai
Yan
Y
Gong
Likun
L
Liu
Linlin
L
Chen
Fangping
F
Xiao
Ying
Y
Wu
Xiongfei
X
Li
Yan
Y
Xue
Xiang
X
Ren
Jin
J
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D034341:Aristolochic Acids / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015153:Blotting, Western; D001865:Bongkrekic Acid / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D007684:Kidney Tubules / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008928:Mitochondria / Q000187:drug effects*; D000226:Mitochondrial ADP, ATP Translocases / Q000235:genetics / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D034341:Aristolochic Acids; D001865:Bongkrekic Acid; D016572:Cyclosporine; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D000226:Mitochondrial ADP, ATP Translocases; C000228:aristolochic acid I; D053148:Caspase 3