Role of extracellular signal-regulated kinases (ERK) in leptin-induced hypertension.
We investigated if extracellular signal-regulated kinases (ERK) and oxidative stress are involved in the pathogenesis of arterial hypertension induced by chronic leptin administration in the rat. Leptin was administered at a dose of 0.25 mg/kg twice daily s.c. for 4 or 8 days. Blood pressure (BP) was higher in leptin-treated than in control animals from the third day of the experiment. The superoxide dismutase (SOD) mimetic, tempol, normalized BP in leptin-treated rats on days 6, 7 and 8, whereas the ERK inhibitor, PD98059, exerted a hypotensive effect on days 3 through 6. Leptin increased ERK phosphorylation level in renal and aortic tissues more markedly after 4 than after 8 days of treatment. In addition, leptin reduced urinary Na(+) excretion and increased renal Na(+),K(+)-ATPase activity, and these effects were abolished on days 4 and 8 by PD98059 and tempol, respectively. The levels of NO metabolites and cGMP were reduced in animals receiving leptin for 8 days. Markers of oxidative stress (H(2)O(2) and lipid peroxidation products) were elevated to a greater extent after 4 than after 8 days of leptin treatment. In contrast, nitrotyrosine, a marker of protein nitration by peroxynitrite, was higher in animals receiving leptin for 8 days. NADPH oxidase inhibitor, apocynin, prevented leptin's effect on BP, ERK, Na(+),K(+)-ATPase/Na(+) excretion and NO formation at all time points. SOD activity was reduced, whereas glutathione peroxidase (GPx) activity was increased in the group treated with leptin for 8 days. These data indicate that: (1) ERK, activated by oxidative stress, is involved only in the early phase of leptin-induced BP elevation, (2) the later phase of leptin-induced hypertension is characterized by excessive NO inactivation by superoxide, (3) the time-dependent shift from ERK to O(2)(-)-NO dependent mechanism may be associated with reduced SOD/GPx ratio, which favors formation of O(2)(-) instead of H(2)O(2).
Wójcicka
Grazyna
G
Department of Pathophysiology, Medical University, ul. Jaczewskiego 8, 20-090 Lublin, Poland.
Jamroz-Wiśniewska
Anna
A
Widomska
Sylwia
S
Ksiazek
Marta
M
Bełtowski
Jerzy
J
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D007279:Injections, Subcutaneous; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013113:Spin Labels
D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D005419:Flavonoids; D020738:Leptin; D013113:Spin Labels; D009569:Nitric Oxide; D048049:Extracellular Signal-Regulated MAP Kinases; D000254:Sodium-Potassium-Exchanging ATPase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C001803:tempol