Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells.
Cadmium is a potent nephrotoxin that has been shown to induce apoptosis in some cells but also to prevent it under certain circumstances. In several clinical situations and experimental models of injury to the renal glomerulus, pathological proliferation of mesangial cells is followed by resolution involving mesangial cell apoptosis. We investigated the effects of Cd(2+) on rat mesangial cells induced to undergo apoptosis through either the extrinsic receptor-mediated pathway or the intrinsic mitochondrial-dependent pathway. Camptothecin initiated the intrinsic pathway with activation of caspase-9 and caspase-dependent cleavage of procaspase-3. Tumor necrosis factor-alpha (TNF-alpha) initiated caspase-8 activity and cleavage of pro-caspase-3 at the convergence point of the two pathways. However, pro-caspase-8 levels were low, and caspase-9 was also activated in response to TNF-alpha, characteristic of what have been termed type II cells. With both TNF-alpha and camptothecin, concurrent exposure to 10 microM CdCl(2) suppressed DNA laddering, nuclear condensation, and pro-caspase-3 cleavage. It also decreased activity of both caspase-8 and caspase-9, prevented caspase-8-dependent cleavage of the proapoptotic factor Bid, and suppressed release of cytochrome c from mitochondria. At this 10-microM concentration, Cd(2+) was unique among a number of metal ions in preventing DNA fragmentation. We conclude that Cd(2+) is anti-apoptotic in rat mesangial cells, acting by a mechanism that may involve general caspase inhibition. This may have consequences for the resolution of nephritis in situations of mesangial cell hyperproliferation.
Gunawardana
C Geeth
CG
Dept. of Laboratory Medicine and Pathobiology, Medical Sciences Bldg. Rm. 6302, Univ. of Toronto, 1 King's College Circle, Toronto, Ontario, Canada.
Martinez
Raul E
RE
Xiao
Weiqun
W
Templeton
Douglas M
DM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D004249:DNA Damage; D050527:Mesangial Cells / Q000187:drug effects* / Q000502:physiology; D009393:Nephritis / Q000139:chemically induced / Q000503:physiopathology; D051381:Rats
D002104:Cadmium; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases