Atrial natriuretic peptide reduces cyclosporin toxicity in renal cells:: Role of cGMP and heme oxygenase-1

被引:39
作者
Polte, T [1 ]
Hemmerle, A [1 ]
Berndt, G [1 ]
Grosser, N [1 ]
Abate, A [1 ]
Schröder, H [1 ]
机构
[1] Univ Halle Wittenberg, Sch Pharm, Dept Pharmacol & Toxicol, D-06099 Halle Saale, Saale, Germany
关键词
immunosuppression; guanylyl cyclase; antioxidant; bilirubin; LLC-PK1; cells; free radicals;
D O I
10.1016/S0891-5849(01)00761-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 muM) or the antioxidant heme oxygenase (HO) metabolite bilirubin (0.1-10 muM). 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 muM), 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. (C) 2001 Elsevier Science Inc.
引用
收藏
页码:56 / 63
页数:8
相关论文
共 51 条
[1]   INDUCTION OF HEME OXYGENASE IN TOXIC RENAL INJURY - A PROTECTIVE ROLE IN CISPLATIN NEPHROTOXICITY IN THE RAT [J].
AGARWAL, A ;
BALLA, J ;
ALAM, J ;
CROATT, AJ ;
NATH, KA .
KIDNEY INTERNATIONAL, 1995, 48 (04) :1298-1307
[2]  
AHMED SS, 1993, J PHARMACOL EXP THER, V265, P1047
[3]  
ALAM J, 1992, J BIOL CHEM, V267, P21894
[4]  
Appleton SD, 1999, DRUG METAB DISPOS, V27, P1214
[5]   Oxidant mechanisms in toxic acute renal failure [J].
Baliga, R ;
Ueda, N ;
Walker, PD ;
Shah, SV .
DRUG METABOLISM REVIEWS, 1999, 31 (04) :971-997
[6]   PREVENTION OF ISCHEMIA/REPERFUSION INJURY IN THE RAT-LIVER BY ATRIAL-NATRIURETIC-PEPTIDE [J].
BILZER, M ;
WITTHAUT, R ;
PAUMGARTNER, G ;
GERBES, AL .
GASTROENTEROLOGY, 1994, 106 (01) :143-151
[7]   Prevention of Kupffer cell-induced oxidant injury in rat liver by atrial natriuretic peptide [J].
Bilzer, M ;
Jaeschke, H ;
Vollmar, AM ;
Paumgartner, G ;
Gerbes, AL .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 1999, 276 (05) :G1137-G1144
[8]   THE BENEFICIAL EFFECT OF ATRIAL-NATRIURETIC-PEPTIDE ON CYCLOSPORINE NEPHROTOXICITY [J].
CAPASSO, G ;
ROSATI, C ;
CIANI, F ;
GIORDANO, DR ;
RUSSO, F ;
DESANTO, NG .
AMERICAN JOURNAL OF HYPERTENSION, 1990, 3 (03) :204-210
[9]   INCREASED LIPID-PEROXIDATION IN CYCLOSPORINE-TREATED HEART-TRANSPLANT RECIPIENTS [J].
CHANCERELLE, Y ;
DELORGERIL, M ;
VIRET, R ;
CHIRON, B ;
DUREAU, G ;
RENAUD, S ;
KERGONOU, JF .
AMERICAN JOURNAL OF CARDIOLOGY, 1991, 68 (08) :813-816
[10]   Carbon monoxide in vasoregulation - The promise and the challenge [J].
Coceani, F .
CIRCULATION RESEARCH, 2000, 86 (12) :1184-1186