There has been a marked increase in the incidence of autoimmune diseases in the last half-century. While the underlying genetic basis of this class of diseases has recently been elucidated implicating predominantly immune response genes1, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17 producing CD4+ helper T cells (Th17 cells) plays a pivotal role in autoimmune diseases2. Pathogenic IL-23 dependent Th17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS), and genetic risk factors associated with MS are related to the IL23/Th17 pathway1, 2. However, little is known regarding the environmental factors that directly influence Th17 cells. Here we show that increased salt (sodium chloride; NaCl) concentrations found locally under physiological conditions in vivo dramatically boost the induction of murine and human Th17 cells. High-salt conditions activate the p38/MAPK pathway involving the tonicity-responsive enhancer binding protein (TonEBP/NFAT5) and the serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced Th17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt induced Th17 cell development. The Th17 cells generated under high-salt display a highly pathogenic and stable phenotype characterized by the up-regulation of the pro-inflammatory cytokines GM-CSF, TNFα and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen specific Th17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic Th17 cells.

Abstract-The recently cloned (pro)renin receptor [(P)RR] mediates renin-stimulated cellular effects by activating mitogen-activated protein kinases and promotes nonproteolytic prorenin activation. In vivo, (P)RR is said to be blocked with a peptide consisting of 10 amino acids from the prorenin prosegment called the "handle-region" peptide (HRP). We tested whether human prorenin and renin induce extracellular signal-regulated kinase (ERK) 1/2 activation and whether the direct renin inhibitor aliskiren or the HRP inhibits the receptor. We detected the (P)RR mRNA and protein in isolated human monocytes and in U937 monocytes. In U937 cells, we found that both human renin and prorenin induced a long-lasting ERK 1/2 phosphorylation despite angiotensin II type 1 and 2 receptor blockade. In contrast to angiotensin II-ERK signaling, renin and prorenin signaling did not involve the epidermal growth factor receptor. A mitogen-activated protein kinase kinase 1/2 inhibitor inhibited both renin and prorenin-induced ERK 1/2 phosphorylation. Neither aliskiren nor HRP inhibited binding of I-prorenin to (P)RR. Aliskiren did not inhibit renin and prorenin-induced ERK 1/2 phosphorylation and kinase activity. Fluorescence-activated cell sorter analysis showed that, although fluorescein isothiocyanate-labeled HRP bound to U937 cells, HRP did not inhibit renin or prorenin-induced ERK 1/2 activation. In conclusion, prorenin and renin-induced ERK 1/2 activation are independent of angiotensin II. The signal transduction is different from that evoked by angiotensin II. Aliskiren has no (P)RR blocking effect and did not inhibit ERK 1/2 phosphorylation or kinase activity. Finally, we found no evidence that HRP affects renin or prorenin binding and signaling. Key Words: renin Ⅲ prorenin Ⅲ (pro)renin receptor Ⅲ aliskiren Ⅲ signal transduction A liskiren is a recent Food and Drug Administrationapproved, low-molecular weight, direct renin inhibitor that binds to the enzymatically active cleft of renin. Direct renin inhibition in a double-transgenic rat model of high human renin hypertension demonstrated target organ protection. 1,2 A novel (pro)renin receptor [(P)RR] has been cloned that signals when exposed to either renin or prorenin. 3 The (P)RR, correctly termed "RR/ATP6AP2," is a single transmembrane domain protein of 350 amino acids with a large unglycosylated and highly hydrophobic N-terminal domain and a short cytoplasmic tail of Ϸ20 amino acids. The (P)RR is a protein conserved among species. 4 The (P)RR enhances renin catalytic activity and allows prorenin to display catalytic activity without its proteolytic conversion to renin ("nonproteolytic activation"). Such nonproteolytic activation involves unfolding of the prosegment from the enzymatic cleft, mediated by a (P)RR-induced conformational change in the prorenin molecule. This (P)RR-induced prorenin activation could explain how prorenin exerts pathological effects in diabetic patients, where prorenin represents Յ95% of total circulating renin. Nevertheless, this hypothesis remain...

Background-Hypertensive target organ damage, especially cardiac hypertrophy with heart failure and arrhythmia, is a major source of morbidity and mortality. Angiotensin II, a major mediator of hypertension and cardiac damage, has proinflammatory properties. Inflammation and activation of the immune system play a pivotal role in pathogenesis of hypertensive target organ damage. However, the role of immunosuppressive CD4

Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelinoligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis ( antigen presenting cell ͉ blood pressure ͉ chemokine ͉ multiple sclerosis

Abstract-Angiotensin (Ang) II induces vascular injury in part by activating innate and adaptive immunity; however, the mechanisms are unclear. We investigated the role of interferon (IFN

The aim of this review is to summarize and discuss some of the more recent insights as to how immune cells might affect the regulation of blood pressure and the pathogenesis of hypertension-induced target organ damage.

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higher all-cause mortality and incidence of CV events. 2,3 Supplementation of active vitamin D metabolites and vitamin D analogues significantly lowered CV mortality independently of corrections in bone metabolism, thereby implicating direct effects of vitamin D on different pathological mechanisms of CV disease. 4,5 Several studies in the general population also show an inverse relation between 25-D levels and incidence of CV diseases, e.g. the Framingham Offspring Study involving 1739 participants without prior CV disease. Participants with 25-D <15 ng/ml had increased risk of developing the first CV event during the mean of 5.4 years of observation compared with those with 25-D >15 ng/ml. Interestingly, this effect was only evident in participants with hypertension but not in those without hypertension. 6 Furthermore, all-cause mortality and CV mortality are also associated with vitamin D status in the general population. 7 However, in contrast to abundant data on CV risk reduction by vitamin D supplements in patients with CKD, there are only scarce data suggesting the same beneficial effect in general population. A metaanalysis of eight randomized trials involving >40000 participants shows that high-dose vitamin D supplementation (1000 IU/day) non-significantly reduces cardiovascular risk. 8 Further randomized trials are necessary to explore the role of vitamin D supplementation with the aim to prevent CV diseases before its widespread use can be recommended.The link between vitamin D and arterial hypertension is of special interest, since arterial hypertension is one of the major risk factors for CV disease. Large observational studies demonstrated that the prevalence of hypertension is inversely associated with vitamin D status. 9-11 One meta-analysis of eight randomized trials supplementing vitamin D to hypertensive population showed a small and significant reduction in diastolic blood pressure (-3.1 mmHg, 95% confidence interval [CI] -5.5 to -0.6) and a non-significant reduction in systolic blood pressure (-3.6 mmHg, 95% CI -8.0 to 0.7) in the vitamin D-treated subjects compared to placebo-treated subjects. 12 Another meta-analysis showed a non-significant reduction in systolic blood pressure (weighted mean difference -1.9 mmHg) in subjects treated with vitamin D supplementation, but no effect on diastolic blood pressure. 13 Vitamin D was long known to be a major player in calcium homeostasis and bone metabolism, since first being discovered at the beginning of the 20th century as a missing nutrient in children with severe bone demineralization, a disease called rickets. A century later, we are aware of its multiple non-skeletal actions. Vitamin D receptor (VDR) is present in many tissues including immune cells and cardiovascular (CV) target organs. Its activation influences numerous genes involved in cell proliferation, differentiation and function as well as the renin-angiotensin system (RAS).The major sources of vitamin D are our diet, supplementation and sun exposure. Solar UVB radiation converts 7-d...