Role of extracellular signal-regulated kinases (ERK) in leptin-induced hypertension.

Abstract

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).

• Authors: Grazyna Wójcicka, Anna Jamroz-Wiśniewska, Sylwia Widomska, Marta Ksiazek, Jerzy Bełtowski
• Journal: Life sciences (Life Sci) Vol. 82 Issue 7-8 Pg. 402-12 (Feb 13 2008) ISSN: 0024-3205 [Print] Netherlands
• PMID: 18206959 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic N-Oxides
• Enzyme Inhibitors
• Flavonoids
• Leptin
• Spin Labels
• Nitric Oxide
• Extracellular Signal-Regulated MAP Kinases
• Sodium-Potassium-Exchanging ATPase
• 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
• tempol

Topics

• Animals
• Aorta (drug effects, enzymology)
• Blood Pressure (drug effects)
• Cyclic N-Oxides (pharmacology)
• Disease Models, Animal
• Drug Administration Schedule
• Drug Therapy, Combination
• Enzyme Inhibitors (pharmacology)
• Extracellular Signal-Regulated MAP Kinases (antagonists & inhibitors, metabolism)
• Flavonoids (pharmacology)
• Hypertension (chemically induced, enzymology, physiopathology)
• Injections, Subcutaneous
• Kidney (drug effects, enzymology)
• Leptin (pharmacology)
• Male
• Nitric Oxide (metabolism)
• Oxidative Stress (drug effects)
• Phosphorylation
• Rats
• Rats, Wistar
• Sodium-Potassium-Exchanging ATPase (metabolism)
• Spin Labels