Role of PI3K and PKB/Akt in acute natriuretic and NO-mimetic effects of leptin.
Apart from controlling energy balance, leptin, a peptide hormone secreted by white adipose tissue, is also involved in the regulation of cardiovascular function. Previous studies have documented that leptin stimulates natriuresis and nitric oxide (NO) production, but the mechanism of these effects is incompletely elucidated. We examined whether phosphoinositide 3-kinase (PI3K) and its downstream effector, protein kinase B/Akt are involved in acute natriuretic and NO-mimetic effects of leptin in anaesthetized rats. Leptin (1 mg/kg i.v.) induced a marked increase in natriuresis and this effect was abolished by pretreatment with either wortmannin (15 microg/kg) or LY294002 (0.6 mg/kg), two structurally different PI3K inhibitors. Moreover, leptin increased plasma concentration and urinary excretion of NO metabolites, nitrites+nitrates (NO(x)), and of NO second messenger, cyclic GMP. In addition, leptin increased NO(x) and cGMP in aortic tissue. The stimulatory effect of leptin on NO(x) and cGMP was prevented by PKB/Akt inhibitor, triciribine, but not by either wortmannin or LY294002. Triciribine had no effect on leptin-induced natriuresis. Leptin stimulated Akt phosphorylation at Ser(473) in aortic tissue but not in the kidney. These results suggest that leptin-induced natriuresis is mediated by PI3K but not Akt, whereas NO-mimetic effect of leptin results from PI3K-independent stimulation of Akt.
Bełtowski
Jerzy
J
Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland. jerzy.beltowski@am.lublin.pl
Wójcicka
Grazyna
G
Jamroz-Wiśniewska
Anna
A
Borkowska
Ewelina
E
D000818:Animals; D006152:Cyclic GMP / Q000097:blood / Q000652:urine; D007668:Kidney / Q000502:physiology; D020738:Leptin / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D009318:Natriuresis / Q000187:drug effects / Q000502:physiology*; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism* / Q000652:urine; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction
D020738:Leptin; D009569:Nitric Oxide; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D006152:Cyclic GMP