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Metabolic syndrome is an important risk factor for proteinuria and chronic kidney disease independent of diabetes and hypertension; however, the underlying mechanisms have not been elucidated. Aldosterone is implicated in target organ injury of obesity-related disorders. This study investigated the role of aldosterone in the early nephropathy of 17-wk-old SHR/ NDmcr-cp, a rat model of metabolic syndrome. Proteinuria was prominent in SHR/NDmcr-cp compared with nonobese SHR, which was accompanied by podocyte injury as evidenced by foot process effacement, induction of desmin and attenuation of nephrin. Serum aldosterone level, renal and glomerular expressions of aldosterone effector kinase Sgk1, and oxidative stress markers all were elevated in SHR/NDmcr-cp. Mineralocorticoid receptors were expressed in glomerular podocytes. Eplerenone, a selective aldosterone blocker, effectively improved podocyte damage, proteinuria, Sgk1, and oxidant stress. An antioxidant tempol also alleviated podocyte impairment and proteinuria, along with inhibition of Sgk1. As for the mechanisms of aldosterone excess, visceral adipocytes that were isolated from SHR/NDmcr-cp secreted substances that stimulate aldosterone production in adrenocortical cells. The aldosterone-releasing activity of adipocytes was not inhibited by candesartan. Adipocytes from nonobese SHR did not show such activity. In conclusion, SHR/NDmcr-cp exhibit enhanced aldosterone signaling, podocyte injury, and proteinuria, which are ameliorated by eplerenone or tempol. The data also suggest that adipocyte-derived factors other than angiotensin II might contribute to the aldosterone excess of this model.

Abstract-Angiotensin II (AII) is involved in the pathogenesis of both hypertension and insulin resistance, though few studies have examined the relationship between the two. We therefore investigated the effects of chronic AII infusion on blood pressure and insulin sensitivity in rats fed a normal (0.3% NaCl) or high-salt (8% NaCl) diet. AII infusion for 12 days significantly elevated blood pressure and significant insulin resistance, assessed by a hyperinsulinemic-euglycemic clamp study and glucose uptake into isolated muscle and adipocytes. High-salt loading exacerbated the effects of AII infusion significantly. Despite the insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol (PI) 3-kinase, and phosphorylation of Akt were all enhanced by AII infusion. Subsequently, to investigate whether oxidative stress induced by AII contributes to insulin resistance, the membrane-permeable superoxide dismutase mimetic, tempol, was administered to AII-infused rats. Chronic AII infusion induced an accumulated plasma cholesterylester hydroperoxide levels, indicating the increased oxidative stress, whereas the treatment with tempol normalized plasma cholesterylester hydroperoxide levels in AII-infused rats. In addition, the treatment with tempol normalized insulin resistance in AII-infused rats, shown as a decreased glucose infusion rate in the hyperinsulinemic euglycemic clamp study and a decreased insulin-induced glucose uptake into isolated skeletal muscle, as well as enhanced insulin-induced PI 3-kinase activation to those in the control rats. These results strongly suggest that AII-induced insulin resistance cannot be attributed to impairment of early insulin-signaling steps and that increased oxidative stress, possibly through impaired insulin signaling located downstream from PI 3-kinase activation, is involved in AII-induced insulin resistance. Key Words: angiotensin II Ⅲ insulin resistance Ⅲ oxidative stress Ⅲ glucose clamp technique Ⅲ sodium Ⅲ kinase S everal lines of evidence point to an association between hypertension and insulin resistance, 1,2 eg, hypertensive individuals are more likely to become diabetic than normotensive ones. 3 It is therefore notable that angiotensin II (AII) is reportedly involved in the development of both hypertension and insulin resistance, 4 -7 and agents that inhibit the action of AII, ie, angiotensin-converting enzyme inhibitors and type 1 AII (AT1) receptor antagonists, not only reduce blood pressure but also restore insulin sensitivity. 8 -14 It has been suggested that crosstalk between AII-and insulinsignaling pathways underlies AII-induced insulin resistance. According to that model, AII induces tyrosine phosphorylation of insulin receptor substrate (IRS)-1 by Janus kinase 2 (JAK2) associated with the AT1 receptor, thereby attenuating insulin-induced activation of phosphatidylinositol (PI) 3-kinase associated with IRS-1, which in turn diminishes insulin sensitivity. 15,16 However, ...

Hypertension is a leading contributor to cardiovascular mortality worldwide. Despite this, its underlying mechanism(s) and the role of excess salt in cardiorenal dysfunction are unclear. Previously, we have identified cross-talk between mineralocorticoid receptor (MR), a nuclear transcription factor regulated by the steroid aldosterone, and the small GTPase Rac1, which is implicated in proteinuric kidney disease. We here show that high-salt loading activates Rac1 in the kidneys in rodent models of salt-sensitive hypertension, leading to blood pressure elevation and renal injury via an MR-dependent pathway. We found that a high-salt diet caused renal Rac1 upregulation in salt-sensitive Dahl (Dahl-S) rats and downregulation in salt-insensitive Dahl (Dahl-R) rats. Despite a reduction of serum aldosterone levels, salt-loaded Dahl-S rats showed increased MR signaling in the kidneys, and Rac1 inhibition prevented hypertension and renal damage with MR repression. We further demonstrated in aldosterone-infused rats as well as adrenalectomized Dahl-S rats with aldosterone supplementation that salt-induced Rac1 and aldosterone acted interdependently to cause MR overactivity and hypertension. Finally, we confirmed the key role of Rac1 in modulating salt susceptibility in mice lacking Rho GDP-dissociation inhibitor α. Therefore, our data identify Rac1 as a determinant of salt sensitivity and provide insights into the mechanism of salt-induced hypertension and kidney injury.

clinicaltrials.gov Identifier: NCT00225849.

Background-Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of proadrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo. Methods and Results-Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM Ϫ/Ϫ mutation in mice was embryonic lethal without any apparent phenotypic changes, AM ϩ/Ϫ mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM ϩ/ϩ mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt-treated AM ϩ/Ϫ mice, without the AM upregulation that was observed in Ang II/salt-treated AM ϩ/ϩ mice. In AM ϩ/Ϫ mice, Ang II/salt loading increased both urinary excretion of 8-hydroxydeoxyguanosine and isoprostane, markers of oxidative stress. Consistently, immunostaining of both p67phox and gp91phox, subunits of NAD(P)H oxidase and 3-nitrotyrosine, the metabolites of reactive oxygen species (ROS), and the generation of ROS measured by electron spin resonance spectroscopy apparently increased in the Ang II/salt-treated heart. These data suggested that the overproduction of oxidative stress might be involved in the cardiovascular changes induced by Ang II/salt loading. Conclusions-The

Abstract-A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.

Cilnidipine, a dual L-/N-type calcium channel blocker, dilates both efferent and afferent arterioles and is renoprotective. Our multi-center, open-labeled, and randomized trial compared the antiproteinuric effect of cilnidipine with that of amlodipine in hypertensive patients with kidney disease. A group of 339 patients, already receiving renin-angiotensin system inhibitor treatment, were randomly assigned to cilnidipine or amlodipine. The primary endpoint was a decrease in the urinary protein to creatinine ratio. After 1-year of treatment, systolic and diastolic blood pressures were significantly reduced in both groups which did not differ between them. The urinary protein to creatinine ratio significantly decreased in the cilnidipine compared to the amlodipine group. Cilnidipine exerted a greater antiproteinuric effect than amlodipine even in the subgroup whose blood pressure fell below the target level. This study suggests that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in hypertensive patients when coupled with a renin-angiotensin system inhibitor.