Cardiac natriuretic peptides inhibit cyclosporine-induced production of endothelin in cultured rat mesangial cells.
Cyclosporine A (CSA) stimulates vascular endothelial cell production of endothelin-1 (ET-1). The present study was designed to test two hypotheses: (1) CSA stimulates ET-1 secretion in cultured rat mesangial cells, and (2) cardiac natriuretic peptides, atrial and brain natriuretic peptides (ANP and BNP), inhibit the above-mentioned secretion in these cells. CSA stimulated ET-1 secretion in a concentration-dependent manner between 10 and 100 ng/mL. In contrast, high concentrations of CSA (10 and 100 micrograms/mL) were cytotoxic and failed to stimulate ET-1 secretion. Rat ANP (1-28) and rat BNP-45 exhibited clearly concentration-related inhibition of CSA-induced ET-1 secretion. This inhibition by ANP and BNP was paralleed by an increase in the cellular level of cyclic guanosine-3',5'-monophosphate (cGMP). Rat ANP (5-25) was less effective than rat ANP (1-28) with respect to inhibiting ET-1 secretion and increasing cellular cGMP. Addition of a cGMP analog, 8-bromo-cGMP, reduced CSA-induced ET-1 secretion. On the other hand, addition of a cyclic adenosine-3',5'-monophosphate (cAMP) analog, 8-bromo-cAMP, did not affect CSA-induced ET-1 secretion. These findings suggest that CSA in low concentrations stimulates ET-1 production in cultured rat mesangial cells, and that cardiac natriuretic peptides inhibit this stimulated production, probably through a cGMP-dependent process.
Kohno
M
M
First Department of Internal Medicine, Osaka City University Medical School, Japan.
Yokokawa
K
K
Mandal
A K
AK
Horio
T
T
Yasunari
K
K
Takeda
T
T
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology*; D016232:Endothelins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D019208:Brain-Derived Neurotrophic Factor; D016232:Endothelins; D009419:Nerve Tissue Proteins; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; D006152:Cyclic GMP