Renal cell apoptosis induced by nephrotoxic drugs: cellular and molecular mechanisms and potential approaches to modulation.
Apoptosis plays a central role not only in the physiological processes of kidney growth and remodeling, but also in various human renal diseases and drug-induced nephrotoxicity. We present in a synthetic fashion the main molecular and cellular pathways leading to drug-induced apoptosis in kidney and the mechanisms regulating it. We illustrate them using three main nephrotoxic drugs (cisplatin, gentamicin, and cyclosporine A). We discuss the main regulators and effectors that have emerged as key targets for the design of therapeutic strategies. Novel approaches using gene therapy, antisense strategies, recombinant proteins, or compounds obtained from both classical organic and combinatorial chemistry are examined. Finally, key issues that need to be addressed for the success of apoptosis-based therapies are underlined.
Servais
H
H
Faculty of Medicine, Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain-UCL 7370, Avenue E. Mounier 73, Brussels, Belgium. helene.servais@wanadoo.be
Ortiz
A
A
Devuyst
O
O
Denamur
S
S
Tulkens
P M
PM
Mingeot-Leclercq
M-P
MP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002945:Cisplatin / Q000378:metabolism / Q000633:toxicity*; D016572:Cyclosporine / Q000378:metabolism / Q000633:toxicity*; D005839:Gentamicins / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000187:drug effects*; D053858:Metabolic Networks and Pathways; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051437:Renal Insufficiency / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D005839:Gentamicins; D016572:Cyclosporine; D020169:Caspases; D002945:Cisplatin