Leptin is a hormone related to metabolism. It also influences blood pressure, but the mechanisms triggered in this process are not yet elucidated. Angiotensin-I converting enzyme (ACE) regulates cardiovascular functions and recently has been associated with metabolism control and obesity. Here, we used ob/ob mice, a model lacking leptin, to answer the question whether ACE and leptin could interact to influence blood pressure, thereby linking the renin-angiotensin system and obesity. These mice are obese and diabetic but have normal 24 h mean arterial pressure. Our results show that plasma and lung ACE activities as well as ACE mRNA expression were significantly decreased in ob/ob mice. In agreement with these findings, the hypotensive effect produced by enalapril administration was attenuated in the obese mice. Plasma renin, angiotensinogen, angiotensin I, bradykinin, and angiotensin 1-7 were increased, whereas plasma angiotensin II concentration was unchanged in obese mice. Chronic infusion of leptin increased renin activity and angiotensin II concentration in both groups and increased ACE activity in ob/ob mice. Acute leptin infusion restored ACE activity in leptin-deficient mice. Moreover, the effect of an ACE inhibitor on blood pressure was not changed in ob/+ mice during leptin treatment but increased four times in obese mice. In summary, our findings show that the renin-angiotensin system is altered in ob/ob mice, with markedly reduced ACE activity, which suggests a possible connection between the renin-angiotensin system and leptin. These results point to an important interplay between the angiotensinergic and the leptinergic systems, which may play a role in the pathogenesis of obesity, hypertension, and metabolic syndrome.

Abstract-Angiotensin

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BACKGROUND AND PURPOSEKinins are pro-inflammatory peptides that are released during tissue injury, including that caused by inflammatory bowel disease. Herein, we assessed the role and underlying mechanisms through which the absence of kinin B1 receptors exacerbates the development of dextran sulfate sodium (DSS)-induced colitis in mice. EXPERIMENTAL APPROACHB1 and B2 receptor antagonists and B1 receptor knockout mice (B1 -/-) were used to assess the involvement of B1 and B2 receptor signalling in a DSS-colitis. B1 receptor, B2 receptor, occludin and claudin-4 expression, cytokine levels and cell permeability were evaluated in colon from wild-type (WT) and B1 -/-mice. KEY RESULTS DSS-induced colitis was significantly exacerbated in B1-/-compared with WT mice. IL-1b, IFN-g, keratinocyte-derived chemokine and macrophage inflammatory protein-2 were markedly increased in the colon from DSS-treated B1 -/-compared with DSS-treated WT mice. Treatment of WT mice with a selective B1 receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B2 receptor mRNA expression was significantly up-regulated in colonic tissue from the B1 -/-mice after DSS administration. Moreover, treatment with a selective B2 receptor antagonist prevented the exacerbation of colitis in B1 -/-mice following DSS administration. The water-or DSS-treated B1 -/-mice showed a decrease in occludin gene expression, which was partially prevented by the B2 receptor antagonist. CONCLUSIONS AND IMPLICATIONSA loss of B1 receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1 -/-may be associated with compensatory overexpression of B2 receptors, which, in turn, modulates tight junction expression.