Time-dependent transition from H(2)O(2)-extracellular signal-regulated kinase- to O(2)-nitric oxide-dependent mechanisms in the stimulatory effect of leptin on renal Na+/K+/-ATPase in the rat.
1. Recent studies suggest that leptin, a peptide hormone secreted by white adipose tissue, is involved in the pathogenesis of arterial hypertension, in part by regulating renal sodium handling. Previously, we have demonstrated that in normal rats leptin has a time-dependent effect on renal Na(+)/K(+)-ATPase that drives tubular sodium reabsorption. Short-term leptin infusion results in a transient decrease in Na(+)/K(+)-ATPase activity, whereas prolonged administration stimulates the enzyme. 2. In the present study, we investigated whether these acute effects of leptin are preserved in rats with experimentally induced chronic hyperleptinaemia. 3. Hyperleptinaemia was induced by administration of exogenous leptin (0.25 mg/kg twice daily, s.c., for 7 days). Acute effects of leptin in anaesthetized control (normoleptinaemic) and hyperleptinaemic animals was investigated. Leptin was infused into the abdominal aorta proximally to the renal arteries for 0.5, 1, 2 or 3 h. 4. Leptin (1 microg/min per kg) had a time-dependent effect on renal Na(+)/K(+)-ATPase in both the control and hyperleptinaemic groups. The inhibitory effect observed after 0.5 h infusion was impaired in the hyperleptinaemic group. However, in both groups this effect was abolished by the Janus kinase inhibitor tyrphostin AG490 (100 nmol/min per kg), as well as by the phosphatidylinositol 3-kinase inhibitors wortmannin (10 nmol/min per kg) and LY294002 (1 micromol/min per kg). 5. The stimulatory effect of leptin on Na(+)/K(+)-ATPase activity was observed after 3 h of infusion and was of similar magnitude in control and hyperleptinaemic groups. In the control group, the stimulatory effect of leptin was abolished by the NADPH oxidase inhibitor apocynin (1 micromol/min per kg), the H(2)O(2) scavenger catalase (1 mg/min per kg) and the extracellular signal-regulated kinase (ERK) inhibitor PD98059 (100 nmol/min per kg). In contrast, in the hyperleptinaemic group, the stimulatory effect of leptin was abolished by the cGMP analogue 8-bromo-cGMP (100 nmol/min per kg) and by the superoxide dismutase mimetic tempol (100 micromol/min per kg) but was not affected by catalase or PD98059. 6. Leptin increased urinary H(2)O(2) excretion and ERK phosphorylation in the renal tissue only in the control group. 7. The results suggest that the acute stimulatory effect of leptin on renal Na(+)/K(+)-ATPase is mediated by divergent mechanisms depending on the chronic leptin level (i.e. by H(2)O(2)-dependent stimulation of ERK in normoleptinaemic animals and by superoxide-dependent impairment of the nitric oxide-cGMP pathway in hyperleptinaemic rats).
Marciniak
Andrzej
A
Department of Pathophysiology, Medical University, Lublin, Poland.
Borkowska
Ewelina
E
Kedra
Anna
A
Rychlik
Monika
M
Beltowski
Jerzy
J
D000098:Acetophenones / Q000494:pharmacology; D000818:Animals; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology* / Q000652:urine; D007202:Indicators and Reagents; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000494:pharmacology*; D016877:Oxidants / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism*; D013113:Spin Labels; D013268:Stimulation, Chemical; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000098:Acetophenones; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D016166:Free Radical Scavengers; D006861:Hydrogen Peroxide; D007202:Indicators and Reagents; D053612:Janus Kinases; D020738:Leptin; D009569:Nitric Oxide; D016877:Oxidants; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000254:Sodium-Potassium-Exchanging ATPase; D013113:Spin Labels; D013482:Superoxide Dismutase; D013481:Superoxides; C056165:acetovanillone; C001803:tempol