Discussion

    The major findings of the present study were the following: (1) adiponectin supplementation reduced the SBP of spontaneously hypertensive obese KKAy mice accompanied by increased levels of plasma NO metabolites; (2) salt-fed adiponectin KO mice developed hypertension, independent of obesity and insulin resistance, accompanied by reduced mRNA levels of eNOS and PGIS in aorta and eNOS in kidney and lower levels of eNOS and PGIS metabolites in plasma than salt-fed WT mice; (3) adenoviral delivery of adiponectin improved the hypertension and reversed the reduced mRNA levels of eNOS and PGIS in aorta of salt-fed KO mice; and (4) L-NAMEinduced elevation of blood pressure was not observed in KO mice.

    Obesity confers a higher risk of hypertension.2628 Recently, numerous reports have demonstrated that dysregulated production of adipocytokines is involved in the pathophysiology of obesity-related disorders.13 The adipocytokine adiponectin has antiatherosclerotic and antidiabetic properties, and the plasma adiponectin levels are significantly low in obese patients, especially those with visceral fat accumulation.19 Accumulating evidence suggests that visceral fat obesity is precedent and causative of hypertension and cardiovascular disease in metabolic syndrome.33 In our recent analysis, hypoadiponectinemia was an independent risk factor of hypertension in human subjects, independent of obesity and insulin resistance.20 In addition, we reported recently that subjects with I164T mutation of adiponectin gene, who exhibited remarkable hypoadiponectinemia, had higher prevalence of coronary artery disease and hypertension unrelated to obesity.20,22 These findings suggest that hypoadiponectinemia contributes directly to the development of hypertension in humans. Next, we further investigated the role of adiponectin on blood pressure in the mouse model. Adiponectin KO mice did not display the phenotype of the metabolic syndrome under normal diet. On high-fat/high-sucrose diet, however, the KO mice developed severe insulin resistance.10 In addition, the KO mice showed delayed clearance of free fatty acid in plasma and low levels of fatty-acid transport protein 1 mRNA in muscle, although no differences were observed in total cholesterol levels and triglyceride levels in plasma.10,23 On high-fat/high-sucrose/high-salt diet, the KO mice developed hypertension and diabetes mellitus with impaired acetylcholine-induced vasorelaxation of aortic rings.23 In the present study, we showed that obese KKAy mice had hypoadiponectinemia and that adiponectin supplementation ameliorated the hypertension in these mice. In addition, adiponectin KO mice developed hypertension without insulin resistance when maintained on a high-salt diet. These results suggest that hypoadiponectinemia, per se, is not sufficient for the development of hypertension but contributes to its development under insulin resistance and/or salt overload, although further studies are necessary to determine the blood pressure response to various doses of adiponectin.

    In vascular endothelial cells, we have reported that adiponectin promoted the phosphorylation of AMP-activated protein kinase, protein kinase Akt/protein kinase B, and eNOS and that the adiponectin-AMP-activated protein kinase-Akt-eNOS signal was essential for the antiapoptotic and angiogenic effects.24,25 It has been reported that some polymorphism of the human PGIS gene was an independent risk for systolic hypertension34 and that PG I2-deficient mice developed hypertension with the thickening of arterial walls.35 Furthermore, an interaction between NO and PG pathways has been reported.36 In this study, we demonstrated that adiponectin KO mice exhibited salt-induced hypertension accompanied by reduced mRNA levels of eNOS and PGIS in aorta and eNOS in kidney. In addition, adenoviral delivery of adiponectin improved the salt-induced hypertension and reversed the reduced mRNA levels of eNOS and PGIS in aorta of KO mice. In addition, L-NAME had no effect on SBP in adiponectin KO mice under a high-salt diet. On the other hand, there were no significant differences in plasma Na, Cl, K, angiotensin II, aldosterone, and leptin concentrations, in total urinary catecholamines, and in the mRNA levels of angiotensinogen and leptin in white adipose tissue, angiotensinogen in liver, and renin and epithelial sodium channel in kidney between salt-fed KO and WT mice, although it is possible that other mechanisms are involved in the development of hypertension. Thus, the present study suggests that the impaired adiponectineNOSPGIS pathway in the systemic vasculature might be, at least in part, associated with the hypertension of salt-fed adiponectin KO mice, although further studies are necessary to elucidate the precise mechanism.

    In conclusion, we demonstrated in the present study that adiponectin supplementation reduced blood pressure both in obese KKAy mice and salt-fed adiponectin KO mice without affecting the insulin-resistant state. Both KKAy mice and salt-fed adiponectin KO mice developed hypertension accompanied by reduced mRNA levels of eNOS in aorta and kidney and low NO metabolite levels in plasma. These results suggest that hypoadiponectinemia contributes to the development of obesity-related hypertension via a direct effect on vasculature, in addition to its effect on insulin resistance, and that adiponectin supplementation is a potentially useful therapeutic modality for hypertension, as well as insulin resistance in the metabolic syndrome.