Atrial natriuretic peptide reduces cyclosporin toxicity in renal cells: role of cGMP and heme oxygenase-1.
Using cultured proximal renal tubular epithelial cells (LLC-PK1), the present study investigates the effect of atrial natriuretic peptide (ANP) on cytotoxicity induced by cyclosporin A (CsA). Preincubation with ANP (1-100 nM) protected LLC-PK1 cells from CsA-induced toxicity in a concentration-dependent manner. A cytoprotective effect comparable to ANP was observed when preincubating the cells with 8-bromo cGMP (1-100 microM) or the antioxidant heme oxygenase (HO) metabolite bilirubin (0.1-10 microM). ANP or cGMP produced increases in HO-1 protein levels at concentrations that were also effective in cellular protection. Moreover, incubation with ANP or 8-bromo cGMP led to increased HO activity, i.e., formation of bilirubin in the cell lysate (up to 3-fold over basal). Tin protoporphyrin-IX (SnPP; 19 microM), an inhibitor of HO activity, completely abolished ANP-induced cytoprotection. Our results demonstrate that HO-1 is a cellular target of ANP and cGMP in renal cells. HO-1 induction and ensuing formation of antioxidant metabolites may be a novel pathway by which ANP protects from CsA-dependent nephrotoxicity and preserves renal function.
Polte
Tobias
T
Department of Pharmacology and Toxicology, School of Pharmacy, Martin Luther University, Wolfgang-Langenbeck-Strasse 4, 06099 Halle (Saale), Germany.
Hemmerle
Anke
A
Berndt
Georg
G
Grosser
Nina
N
Abate
Aida
A
Schröder
Henning
H
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D001663:Bilirubin / Q000096:biosynthesis / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000187:drug effects / Q000378:metabolism*; D051547:Heme Oxygenase-1; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013552:Swine
D017382:Reactive Oxygen Species; C016276:8-bromocyclic GMP; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D006152:Cyclic GMP; D001663:Bilirubin