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Purpose: Aldosterone proinflammatory/profibrotic effects are mediated by the induction of mononuclear leucocytes (MNL) to express oxidative stress (OxSt)-related proteins, such as p22 phox , and by the activation of RhoA/Rho kinase pathway. Gitelman's syndrome (GS), an autosomal recessive tubulopathy, is an interesting opposite model to hypertension, being characterized by hypokalemia, activation of renin-angiotensin-aldosterone system yet normo/hypotension and lack of cardiovascular-renal remodeling. We aimed to evaluate the proinflammatory/profibrotic effect of aldosterone in MNL of 6 GS patients compared with 6 healthy subjects (HS)., Methods: p22 phox expression and MYPT-1 phosphorylation status, a marker of RhoA/Rho kinase pathway activation, were evaluated in MNL of GS patients and HS at baseline and after incubation with aldosterone (1 × 10 -8  M) alone or with canrenone (1 × 10 -6  M)., Results: At basal condition, p22 phox expression was significantly higher in HS than in GS patients (1.02 ± 0.05 densitometric unit (du) vs 0.40 ± 0.1 du, respectively). Aldosterone significantly increased p22 phox expression in HS and this effect was reversed by coincubation with canrenone (1.4 ± 0.05 du and 1.09 ± 0.03 du, respectively). No significant change was reported in GS after incubation of MNL with aldosterone and/or canrenone compared with basaline. Even MYPT-1 phosphorylation was significantly higher in HS compared with GS patients at basal condition (1.16 ± 0.1 du vs 0.69 ± 0.07, respectively). Aldosterone significantly increased MYPT-1 phosphorylation only in HS (1.37 ± 0.1 du vs 0.83 ± 0.12 du in GS)., Conclusions: GS patients seem to be protected by the OxSt status induced by aldosterone and revealed in HS. This human model could provide additional clues to highlight the proinflammatory/cardiovascular remodeling effects of aldosterone.

Hemodiafiltration with regeneration of ultrafiltrate (HFR) has a positive impact on inflammation and oxidative stress (OxSt), risk factors for cardiovascular disease (CVD), the most common cause of excess morbidity and mortality for end-stage renal disease (ESRD) patients. However, studies have been of limited duration. This study extends our previous study of HFR effects by evaluating the effect on mononuclear cell protein expression of heme-oxygenase-1 (HO-1), induced by OxSt, and inducible subunit of nitric oxide synthase (iNOS), and plasma level of interleukin-1β (Il-1β) and oxidized low-density lipoproteins (OxLDL), marker of OxSt, for a 12-month period. Fourteen ESRD patients stable on hemodialysis over a period of at least 2 years and on conventional bicarbonate dialysis were switched to be treated with HFR. Blood samples were collected at baseline, after 3, 6, 9 and 12 months. HO-1 and iNOS protein expression were evaluated by Western blot, OxLDL by enzyme-linked immunosorbent assay (ELISA), and Il-1β by enzyme amplified sensitivity immumoassay assay. HFR significantly increased HO-1 at the 9 and 12 months (ANOVA = P < 0.00001): 0.17 ± 0.11 (baseline) versus 0.48 ± 0.20, P < 0.043 and 0.59 ± 0.32, P < 0.004, respectively. Il-1β declined (ANOVA = P < 0.0001) since the 3 months from 169.92 ± 92.39 pg/mL (baseline) to 39.03 ± 10.01 (12 months), P < 0.0001. HFR also reduced plasma OxLDL: 475.4 ± 110.8 ng/mL (baseline) versus 393.1 ± 101.9 ng/mL (12 months), P < 0.04. iNOS showed no changes upon HFR treatment. These results together with our previous results indicate that HFR improves OxSt and inflammation. Given the strong relationships between OxSt and inflammation with CVD, their reduction might provide a beneficial impact by reducing the risk of atherosclerotic CVD in dialysis patients., (© 2010, Copyright the Authors. Artificial Organs © 2010, International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Background: Inflammation has been increasingly recognized as playing a critical role in hypertension and atherosclerosis as reflected by overexpression and increased production of a variety of pro-inflammatory mediators. As angiotensin II (Ang II) also plays a major role in these diseases, the relationship between inflammation and Ang II has drawn increasing scrutiny. This study explores Ang II effects in Bartter's and Gitelman's syndromes (BS/GS) which do not develop hypertension and related cardiovascular remodelling and atherosclerosis, in spite of high Ang II levels and activation of the renin-angiotensin-aldosterone system while the NO system is up-regulated., Methods: We evaluated the plasma levels of inflammation-associated markers, C-reactive protein (CRP), serum amyloid A (SAA), vascular cell adhesion molecules (VCAM) and intercellular adhesion molecules (ICAM), and the inflammation-related cytokines interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) using immunonephelometric and ELISA-based assays., Results: The study demonstrated that all markers of inflammation except TNF-alpha, were unchanged in BS/GS (2.51+/-0.62 mg/l in BS/GS vs 1.7+/-0.6 in controls for CRP; 4.56+/-1.09 mg/l in BS/GS vs 4.51+/-1.0 for SAA; 1.84+/-0.27 ng/l in BS/GS vs 2.1+/-0.3 for IL-6; 449+/-83 ng/ml in BS/GS vs 410+/-92 for VCAM and 234+/-26 ng/ml in BS/GS vs 185+/-22 for ICAM), while TNF-alpha was increased (10.5+/-2.03 vs 3.68+/-0.2, P = 0.0001)., Conclusions: The results of this study stress the critical role played by Ang II in controlling vascular biology including inflammation-related processes as well as highlighting the utility of BS/GS in investigating these pathways.

Background and aims Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects. Methods and results In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1 , mTOR , p53 , p66Shc , SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo. Conclusion In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials.gov Identifier NCT01765946 – January 2013. [ABSTRACT FROM AUTHOR]

The article examines the inflammation status through the evaluation of factors included in angiotensin II signaling involved in inflammation in Bartter's/Gitelman's syndrome patients. Results reveal unchanged phosphorylated extracellular signal-regulated kinase (pERK)/ERK ratio and p66shc compared to controls while IκB, the inhibitory subunit of nuclear factor-κB, was increased. This supports a connection between inflammation and hypertension.