Gitelman syndrome (GS) is a rare, salt-losing tubulopathy characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. The disease is recessively inherited, caused by inactivating mutations in the SLC12A3 gene that encodes the thiazide-sensitive sodium-chloride cotransporter (NCC). GS is usually detected during adolescence or adulthood, either fortuitously or in association with mild or nonspecific symptoms or both. The disease is characterized by high phenotypic variability and a significant reduction in the quality of life, and it may be associated with severe manifestations. GS is usually managed by a liberal salt intake together with oral magnesium and potassium supplements. A general problem in rare diseases is the lack of high quality evidence to inform diagnosis, prognosis, and management. We report here on the current state of knowledge related to the diagnostic evaluation, follow-up, management, and treatment of GS; identify knowledge gaps; and propose a research agenda to substantiate a number of issues related to GS. This expert consensus statement aims to establish an initial framework to enable clinical auditing and thus improve quality control of care.

Low expression of RGS2 contributes to increased G-protein-coupled signaling in hypertensive patients. The allele G is associated with low RGS2 expression and blood pressure increase in humans.

RhoA/Rho-kinase signaling and its relationship/balance with the nitric oxide level, angiotensin II and vasopressors for cardiovascular pathophysiology is of increasing importance, and its involvement goes far beyond blood pressure regulation. The deep involvement of this pathway in cardiovascular biology is now known to include a wide spectrum of conditions relating to the long-term complications of hypertension, and in general of cardiovascular pathophysiology, such as changes in cardiovascular structure (remodeling) and the induction of atherosclerosis, involvement in the pathophysiological relationships between inflammation and hypertension, and in those between hypertension, glucose metabolism and insulin resistance. Studies from our laboratory have made an important contribution to the understanding of the cellular and molecular mechanisms mediated by the RhoA/Rho-kinase pathway, which include all the aspects of cardiovascular pathophysiology in which this pathway plays a role. In addition, if it is considered that our contribution to the clarification of these mechanisms only comes from studies in humans, their impact on the scenario of the RhoA/Rho-kinase pathway's biology, essentially supported by studies 'in vitro' or in animal models, is immediate. This review examines all the aspects of RhoA/Rho-kinase signaling in the light of the available data, and gives an updated and useful overall picture of its involvement in cardiovascular pathophysiology.

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Oxidative stress plays a role in cardiovascular dysfunction. This is of interest in diabetes, a clinical condition characterized by oxidative stress and increased prevalence of cardiovascular disease. The role of p66(shc) in oxidative stress-related response has been demonstrated by resistance to and reduction of oxidative stress and prolonged lifespan in p66(shc-/-) mice. In this study we assess p66(shc) gene expression in peripheral blood mononuclear cells (PBM) from type 2 diabetic patients and healthy subjects. The p66(shc) mRNA level was assessed using RT-PCR with two sets of primers mapping for different p66(shc) regions. p66(shc) is expressed in both monocytes and lymphocytes. The level of p66(shc) mRNA was significantly higher in type 2 diabetic patients compared with controls (0.38 +/- 0.07 densitometric units vs. 0.13 +/- 0.08; P < 0.0001). In addition, total plasma 8-isoprostane levels, a marker of oxidative stress, were higher in type 2 diabetics (0.72 +/- 0.04 ng/ml) than in normal subjects (0.43 +/- 0.04, P < 0.001) and were significantly correlated to the p66(shc) mRNA level in PBM from type 2 diabetics (r(2) = 0.47; P = 0.0284). In conclusion, diabetes induces p66(shc) gene expression in circulating PBM; this up-regulation in expression is significantly associated with markers of oxidative stress. p66(shc) gene expression in PBM may represent a useful tool to investigate the oxidative stress involved in the pathogenesis of long-term diabetic complications.

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Hypertensive kidney disease classically entails nephroangiosclerosis and hyalinosis with glomerular damage. However, in recent years, several evidences showed that high blood pressure also injures tubular cells, inducing epithelial-to-mesenchymal transition and tubulointerstitial fibrosis. Recently investigated mechanisms are also podocyte effacement and loss, which lead to denudation of the glomerular basement membrane and focal adhesion of the tufts to the Bowman's capsule, with reduced filtration and scars. Starting from the classic concept of nephroangiosclerosis, this review examines the recently emerged knowledge of new biochemical and molecular mechanisms underlying the kidney damage in hypertension and discusses how viable podocytes or podocyte-deriving proteins are promising tools for early diagnosis of renal remodelling in hypertension.

Studies in patients with Bartter's and Gitelman's syndromes performed in the last 10 years have provided important insights into the mechanistic details of relevant pathways of angiotensin II signaling and vascular tone regulation, therefore making these syndromes a good human model to gain insight into the mechanisms responsible for maintaining/controlling vascular tone. Extensive studies of patients with Bartter's/Gitelman's syndromes have, in fact, shown biochemical abnormalities of angiotensin II short- and long-term cell signaling, which depict a mirror image of those found in hypertension. The information obtained from the study of this human model of altered vascular tone regulation show that it can be used to gather more general data and/or confirm mechanistic details of the cellular and biochemical events involved in the pathophysiology of vascular tone control and to shed light on the multiplicity of the angiotensin II signaling-related mechanisms responsible for the pathophysiology of hypertension and its long-term complication such as cardiovascular remodeling and atherogenesis.