Tissue Renin-angiotensin System Activity Research Articles

Abstract 100: Activation Of The Skin Renin-angiotensin System Contributes To The Development Of Hypertension

Recent studies suggest skin vasoconstriction and sodium (Na + ) accumulation are associated with hypertension. The skin has a localized renin-angiotensin system (RAS), a key regulator of blood pressure (BP), but its functional role remains unclear. This study aims to investigate the role of skin RAS in hypertension. Skin tissue from 32 individuals, including patients with hypertension, was used to evaluate the association between skin RAS component expression and office BP. Among the RAS components, skin expression of ATRAP (type-1 angiotensin II (Ang II) receptor (AT1R)-associated protein), which selectively inhibits pathological AT1R signaling, was inversely correlated with systolic and diastolic BP (R 2 = 0.12, P < 0.05; R 2 = 0.20, P < 0.05, respectively). To investigate the causal relationship between skin ATRAP and hypertension, mice lacking ATRAP in skin keratinocytes (KO: K14 Cre ;ATRAP flox ) were generated. Telemetry analysis showed that Ang II (500 ng/kg/min)-induced hypertension and related cardiac hypertrophy was exacerbated in KO mice compared to control mice (mean BP, 123.3 ± 4.7 vs. 132.6 ± 3.1 mmHg, n = 5, P < 0.05; heart/body weight, 4.7 ± 0.4 vs. 5.2 ± 0.7, n = 11-12, P < 0.05). KO mice showed increased skin expression of angiotensinogen and AT1R ( P < 0.05 for each; n = 11-12), while those in the kidneys and heart were similar in both groups, suggesting skin-specific enhancement of tissue RAS activity. AT1R blocker treatment eliminated exaggerated Ang II-induced hypertension and enhancement of skin RAS activity in KO mice. Sympathetic nerve activity, plasma volume, and skin Na + content did not differ between the groups. In KO mice, urine volume per water intake increased ( P < 0.001), despite similar body weight changes in both groups, suggesting decreased extra-renal water loss. Consistent with these findings, skin blood flow (22.6 ± 3.8 vs. 16.5 ± 4.5 AU, P < 0.001) and transepidermal water loss (9.0 ± 1.9 vs. 6.5 ± 1.9 g/m 2 /h, P < 0.01) were decreased in KO mice. These differences, including exaggerated Ang II-induced hypertension, were eliminated by skin vasodilation via body temperature elevation. In conclusion, enhanced skin RAS activity contributes to BP elevation via skin vasoconstriction. Skin RAS may be a novel target for treating hypertension.

Effect of Vitamin D on Urinary Angiotensinogen Level in Early Diabetic Nephropathy.

Background:Urinary angiotensinogen (UAGT) is supposed to be a marker of activation of the intrarenal renin– angiotensin system (RAS) system in early diabetic nnephropathy (EDN). Vitamin D has been studied as a negative regulator of the circulating and tissue RAS activity, so its supplementation may prevent the progression of diabetic nephropathy (DN). This study was planned to assess the RAS activation and effect of vitamin D supplementation in EDN progression by estimating the UAGT level.Methods:A total of 103 EDN subjects were randomized in two groups to receive either cholecalciferol (54) or matching placebo (49) in a double-blind manner. All were subjected to routine investigations, urinary albumin-to-creatinine ratio (UACR), UAGT, vitamin D, and intact parathyroid hormone (iPTH) at the 0 and 6 months. A total 40 healthy controls were also included for assessment of the same investigations at 0 month.Results:Significant reduction of UACR, UAGT, and iPTH level were corroborated with an increase in 25(OH) vitamin D level from 0 to 6 months (all four P < 0.001). After 6 months, the median [interquartile range (IQR)] of UAGT and UACR levels was significantly lower in the cholecalciferol group as compared to placebo group (p < 0.001 and P = 0.04, respectively). The median UAGT level was significantly higher in patients with EDN (cholecalciferol & placebo Group) than control group at 0 month (p = 0.001).Conclusion:Significantly higher UAGT levels in EDN supports the role of intrarenal RAS activation. A significant decrease in UAGT level in the cholecalciferol group supports the beneficial role of vitamin D supplementation in the progression of EDN.

ATRAP Expression in Brown Adipose Tissue Does Not Influence the Development of Diet-Induced Metabolic Disorders in Mice.

Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAPfl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAPadipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAPfl/fl mice, ATRAPadipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAPfl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAPadipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders.

Receptor-associated prorenin system contributes to development of inflammation and angiogenesis in proliferative diabetic retinopathy.

The renin-angiotensin system (RAS) plays a potential role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor of several diseases including diabetes. So far, using animal disease models, we have shown molecular mechanisms, in which tissue RAS stimulates retinal angiogenesis, and the critical roles of (pro)renin receptor [(P)RR] in retinal RAS activation and its concurrent intracellular signal transduction, referred to as the receptor-associated prorenin system (RAPS). Moreover, we recently reported that the protein levels of prorenin and soluble (P)RR increased in the vitreous fluids obtained from patients with proliferative diabetic retinopathy (PDR), suggesting the association of (P)RR with vascular endothelial growth factor (VEGF)-driven angiogenic activity in human PDR, and also showed a close relationship between the vitreous renin activity and VEGF-induced pathogenesis of diabetic retinopathy. Our data using animal disease models and human clinical samples suggest that both vitreous RAS and retinal RAPS play critical roles in the molecular pathogenesis of diabetic retinopathy.

Abstract P146: Serum Soluble (Pro)Renin Receptor Levels in Patients Undergoing Hemodialysis

Background: The (pro)renin receptor [(P)RR] plays an important role in regulating the tissue renin-angiotensin system (RAS) through the non-proteolytic activation of prorenin, the precursor of renin. (P)RR is cleaved by furin to generate soluble (P)RR [s(P)RR], which is secreted into the extracellular space, and serum s(P)RR has been reported to reflect the status of tissue RAS. Hemodialysis (HD) patients have poor prognosis due to increased prevalence of cardiovascular diseases resulting from severe atherosclerosis. It is speculated that activation of tissue RAS by (P)RR may be associated with this condition, it remains speculative. In the present study, we investigated the relationships between serum s(P)RR levels and background factors including indices of atherosclerosis in HD patients. Methods: Serum s(P)RR levels were measured in 258 maintenance HD patients and these values were compared with 25 subjects with normal renal function. Western blot analysis was done using HD waste water samples, and clearance of s(P)RR through the membrane of dialyzer was examined. Furthermore, relationships between serum s(P)RR levels and background factors were assessed in HD patients. Results: Serum s(P)RR levels were significantly higher in HD patients (30.4±6.1 ng/ml) than those in subjects with normal renal function (16.5±4.3, P&lt;0.0001). s(P)RR was detected in HD waste water by Western blot analysis, and the clearance of s(P)RR and creatinine were 56.9±33.5 and 147.6±9.50 ml/min, respectively. Serum (P)RR levels were significantly higher in those with ankle-brachial index (ABI) of &lt; 0.9, an indicator of severe stenosis or obstruction of lower limb arteries, than those of ≧0.9 (32.2±5.9 and 30.1±6.2 ng/ml, respectively; P&lt;0.05). The association between low ABI and high serum s(P)RR levels were observed even after the correction with age, history of smoking, HbA1c, and LDL-C. Conclusions: Serum s(P)RR levels are significantly higher in HD patients when compared with subjects with normal renal function, although s(P)RR are dialyzed to some extent. High serum s(P)RR levels may be associated with atherosclerosis independent of other risk factors, suggesting that serum s(P)RR could be used as a marker for atherosclerotic condition in HD patients.

Uric acid induces oxidative stress via an activation of the renin–angiotensin system in 3T3-L1 adipocytes

Hyperuricemia is recently reported involving in various obesity-related cardiovascular disorders, especially hypertension. However, the underlying mechanisms are not completely understood. In the present study, we investigated whether uric acid upregulates renin-angiotensin system (RAS) expression in adipocytes. We also examined whether RAS activation plays a role in uric acid-induced oxidative stress in adipocytes. The adipocytes of different phenotypes were incubated with uric acid for 48h, respectively. Losartan (10(-4)M) or captopril (10(-4)M) was used to block adipose tissue RAS activation. mRNA expressions of angiotensinogen (AGT), angiotensin-converting enzyme-1 (ACE-1), renin, angiotensin type 1 receptor (AT1R), and angiotensin type 2 receptor (AT2R) were evaluated with real-time PCR. Angiotensin II concentrations in supernatant were measured by ELISA. Intracellular reactive species (ROS) levels were measured by fluorescent probe DCFH-DA, DHR, or NBT assay. The uric acid upregulated both RAS (AGT, ACE1, renin, AT1R, and AT2R) mRNA expressions and angiotensin II protein secretion and caused a significant increase in ROS production in 3T3-L1 adipocytes. These effects could be prevented by RAS inhibitors, either losartan or captopril. RAS activation has been causally implicated in oxidative stress induced by uric acid in 3T3-L1 adipocytes, suggesting a plausible mechanism through which hyperuricemia contributes to the pathogenesis of obesity-related cardiovascular diseases.

Novel Molecular Angiotensin Converting Enzyme and Angiotensin Receptor Imaging Techniques

Angiotensin II (AII), an octapeptide member of the renin-angiotensin system (RAS), is formed by the enzyme angiotensin converting enzyme (ACE) and exerts adverse cellular effects through an interaction with its type 1 receptor (AT1R). Both ACE inhibitors and angiotensin receptor blockers (ARB) mitigate the vasoconstrictive, proliferative, proinflammatory, proapoptotic, and profibrotic effects of AII and are widely used as effective anti-remodeling agents in clinical practice. Prediction of individual response to these agents, however, remains problematic and is influenced by many factors including race, gender, and genotype. In addition, systemic and tissue RAS activity do not correlate closely. This report summarizes the results of on-going attempts to noninvasively determine tissue ACE activity and AT1R expression using novel nuclear tracers. It is hoped that the availability of such imaging techniques improve treatment of heart failure through more selective pharmacologic intervention and better dose titration of available drugs.

Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats

Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor [(P)RR] blockade with handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels [allowing continuous (P)RR stimulation in vivo], with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might, in fact, act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable.

Possible contribution of (pro)renin receptor to development of gestational diabetes mellitus.

(Pro)renin receptor [(P)RR], a receptor for renin and prorenin, was first cloned in 2002. Since then, the pathophysiological roles of (P)RR have been growing concerns. (P)RR binds renin and prorenin, with two important consequences, nonproteolytic activation of prorenin, leading to the tissue renin-angiotensin system activation and the intracellular signalings. It is now also known to play an important role as vacuolar H(+)-ATPase associated protein, involving in Wnt signaling, main component of embryonic development. Extracellular domain of full-length (P)RR is cleaved in golgi-complex forming soluble (P)RR [s(P)RR]. The s(P)RR is now possible to be measured in human blood and urine. It is now measured in different pathophysiological states, and recent study showed that elevated plasma s(P)RR levels in the early stage of pregnancies are associated with higher incidence of gestational diabetes mellitus later in the pregnancies. Plasma s(P)RR levels of neonates are known to be higher than that of adults. It was also shown that, increased s(P)RR concentrations in cord blood, associated with a lower small for gestational age birth likelihood. These data suggests the involvement of (P)RR in embryo's growth. In this review article, we attempt to figure out the possible pathophysiological roles of the (P)RR in maternal glucose intolerance and embryo's growth, through reviewing previous studies.

Atp6ap2/(Pro)renin Receptor Interacts with Par3 as a Cell Polarity Determinant Required for Laminar Formation during Retinal Development in Mice

(Pro)renin receptor [(P)RR], also known as Atp6ap2, has attracted growing attention as a key molecule for tissue renin-angiotensin system (RAS). In addition to its role in tissue RAS activation, Atp6ap2/(P)RR was originally identified as an accessory subunit for vacuolar H(+)-ATPase (v-ATPase), which is a multisubunit proton pump involved in diverse and fundamental cellular physiology. In this study, to elucidate the physiological function of Atp6ap2/(P)RR during retinal development in mammals, we used Cre-LoxP system to generate photoreceptor-specific conditional knock-out (CKO) mice, and revealed a critical role of Atp6ap2/(P)RR in photoreceptor development. Deletion of photoreceptor Atp6ap2/(P)RR did not affect retinal cell differentiation, but led to laminar disorganization around the outer nuclear layer together with severe dysfunction of photoreceptor cells. In the CKO mice, cell adhesion and polarity molecules, some of which were colocalized with Atp6ap2/(P)RR at the apical edge of the wild-type developing retina, were substantially dispersed together with mislocalization of retinal progenitor cells apart from the apical surface. Among theses molecules, coimmunoprecipitation using retinal homogenates and ATP6AP2/(P)RR-transfected cells showed that Atp6ap2/(P)RR interacted with partitioning defective 3 homolog (PAR3) protein, which is known to function in the Par-atypical protein kinase C (aPKC) system. Furthermore, yeast two-hybrid assays demonstrated direct molecular interaction between ATP6AP2/(P)RR and PAR3. Our present data revealed the novel function of Atp6ap2/(P)RR required for laminar formation during retinal development. We propose that this cellular activity associated with the Par-aPKC system, in addition to the v-ATPase function and tissue RAS activation, is the third biological role of Atp6ap2/(P)RR.

Evaluating hormonal mechanisms of vitamin D receptor agonist therapy in diabetic kidney disease: the VALIDATE-D study

BackgroundInsufficient vitamin D status and increased renin-angiotensin system (RAS) activity have been associated with renal-vascular disease and nephropathy in diabetes. Accumulating evidence indicates that vitamin D receptor (VDR) activation lowers unfavorable RAS activity; however, more human intervention studies evaluating whether this mechanism could influence diabetic kidney disease are needed. We previously reported that both vitamin D levels and genetic variation at the VDR predict human RAS activity, and that vitamin D therapy can lower RAS activity in non-diabetics. The VALIDATE-D study is a randomized, placebo-controlled, intervention study designed to extend these findings by evaluating whether direct VDR activation in diabetes lowers circulating and local renal-vascular tissue RAS activity (Aims 1 and 2) in a manner similar to the action of ACE inhibitors (Aim 3).Methods/DesignForty subjects with type 2 diabetes, microalbuminuria, and without chronic kidney disease will be recruited to undergo detailed assessment of the RAS before and after randomization to calcitriol 0.75 mcg/day or placebo. Primary analyses will evaluate whether calcitriol therapy reduces circulating and renal-vascular tissue-RAS activity in comparison to placebo. All subjects will thereafter be treated with lisinopril and followed for 3.5 months to evaluate whether combination therapy (calcitriol + lisinopril vs. placebo + lisinopril) additively or synergistically improves renal-vascular function, and lowers proteinuria.DiscussionThe VALIDATE-D study is the first human intervention study to evaluate whether direct VDR activation can lower the human RAS in diabetes, compared to the effect of an ACE inhibitor, and whether this mechanism can translate to clinically relevant endpoints for diabetic kidney disease. The outcomes of VALIDATE-D will have major implications for the recommendation of vitamin D supplementation for the primary prevention of kidney complications in diabetes.Trial registrationClinicalTrials.gov, NCT01635062

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

Aims/hypothesis The renin–angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy.

(Pro)renin receptor is associated with angiogenic activity in proliferative diabetic retinopathy

The renin-angiotensin system (RAS) potentially has a role in the development of end-organ damage, and tissue RAS activation has been suggested as a risk factor for diabetic retinopathy. We have recently shown significant involvement of (pro)renin receptor ([P]RR) in retinal inflammation in a rodent model of early diabetes. In this study we aim to elucidate the (P)RR-associated pathogenesis of fibrovascular proliferation, a late-stage angiogenic complication in human diabetic retinopathy. Vitreous fluids from 23 eyes of patients with proliferative diabetic retinopathy (PDR) and 16 eyes of controls with non-diabetic, idiopathic macular diseases (macular hole and epiretinal membrane) were collected. Protein levels of soluble (P)RR were measured by ELISA, and immunofluorescence was performed to assess the localisation of (P)RR and related molecules in fibrovascular tissues from PDR eyes. (P)RR immunoreactivity was detected in neovascular endothelial cells, colocalised with prorenin, phosphorylated extracellular signal-regulated kinase (ERK) and vascular endothelial growth factor (VEGF). Prorenin application to human retinal microvascular endothelial cells significantly upregulated mRNA expression of VEGF, especially the VEGF165 isoform, which was abolished by (P)RR or ERK signalling blockade. Proteases known to cleave (P)RR, including furin, were positive in endothelial cells in fibrovascular tissues. Protein levels of soluble (P)RR in vitreous fluids were higher in PDR eyes than in non-diabetic control eyes, and correlated significantly with vitreous prorenin and VEGF levels and the vascular density of fibrovascular tissues. Our data using human samples provide the first evidence that (P)RR is associated with angiogenic activity in PDR.

Aliskiren penetrates adipose and skeletal muscle tissue and reduces renin–angiotensin system activity in obese hypertensive patients

In animals, the direct renin inhibitor aliskiren showed extensive tissue binding in the kidney and long-lasting renal effects. Aliskiren provides prolonged blood pressure-lowering effects following treatment discontinuation in patients. Therefore, we investigated whether aliskiren attains tissue concentrations sufficient to inhibit local renin-angiotensin system (RAS) activity in patients. We included 10 hypertensive patients with abdominal adiposity in an open-label study. Following 1-2 weeks washout, patients received 2 weeks placebo, then 4 weeks aliskiren 300 mg once daily, followed by 4 weeks washout, and then 4 weeks amlodipine 5 mg once daily. Drug concentrations and RAS biomarkers were measured in interstitial fluid using microdialysis and in biopsies from abdominal subcutaneous adipose and skeletal muscle. We detected aliskiren in all compartments. After 4 weeks of treatment, microdialysate aliskiren concentrations (ng/ml) were 2.4 ± 2.1 (adipose) and 7.1 ± 4.2 (skeletal muscle), similar to plasma concentrations (8.4 ± 4.4); tissue concentrations (ng/g) were 29.0 ± 16.7 (adipose) and 107.3 ± 68.6 (skeletal muscle). Eight weeks after discontinuation, aliskiren was measurable in tissue biopsies but not in plasma or in interstitial fluid. Pooled microdialysate samples from two sets of four patients suggested reduction in tissue angiotensin II with aliskiren but not with amlodipine. In obese hypertensive patients, aliskiren penetrates adipose and skeletal muscle tissue at levels that are apparently sufficient to reduce tissue RAS activity. Furthermore, tissue binding may contribute to aliskiren's prolonged blood pressure-lowering effect following discontinuation.

Regulation of a novel angiotensin II precursor, proangiotensin-12, in the tissues by blockade of the renin–angiotensin system

Regulation of a novel angiotensin II precursor, proangiotensin-12, in the tissues by blockade of the renin–angiotensin system

The Sry3 Y Chromosome Locus Elevates Blood Pressure and Renin-Angiotensin System Indexes

Sex-determining region Y (Sry) is a transcription factor. Our research group has shown that there are multiple copies of Sry in Wistar-Kyoto (WKY) and spontaneous hypertensive (SHR) rats, and that they have novel functions separate from testes determination. We hypothesized that exogenously delivered Sry3 to the normotensive WKY male kidney would activate the renin-angiotensin system (RAS) and raise blood pressure (BP), based on previous in vitro studies. Sry3 or control vector was electroporated to the left kidney of male WKY rats and the following measurements were taken: BP by telemetry, renin-angiotensin measures by radioimmunoassay, plasma and tissue catecholamines by HPLC with electrochemical detection, sodium by flame photometry, and inulin by ELISA. Sry3 increased BP 10 to 20 mm Hg compared with controls (P < 0.01) and produced a significant 40% decrease in urine sodium compared with controls (P < 0.05). Sry3 increased renal angiotensin II and plasma renin activity by >100% compared with controls (P < 0.01 and P < 0.05, respectively). The findings presented here confirm and extend the argument for Sry3 as one of the genes responsible for the SHR hypertensive Y chromosome phenotype and are consistent with increased tissue RAS activity due to Sry3 and increased sodium reabsorption.

Renin-angiotensin system activity in vitamin D deficient, obese individuals with hypertension: An urban Indian study

Background:Elevated renin–angiotensin–aldosterone system (RAAS) activity is an important mechanism in the development of hypertension. Both obesity and 25-hydroxy vitamin D [25(OH)D] deficiency have been associated with hypertension and augmented renin-angiotensin system (RAS) activity. We tried to test the hypothesis that vitamin D deficiency and obesity are associated with increased RAS activity in Indian patients with hypertension.Materials and Methods:Fifty newly detected hypertensive patients were screened. Patients with secondary hypertension, chronic kidney disease, or coronary artery disease were excluded. Patients underwent measurement of vitamin D and plasma renin and plasma aldosterone concentrations. They were divided into three groups according to their baseline body mass index (BMI; normal <25 kg/m2, overweight 25–29.9 kg/m2 and obese ≥30 kg/m2) and 25(OH)D levels (deficient <20 ng/ml, insufficient 20–29 ng/ml and optimal ≥30 ng/ml).Results:A total of 50 (male:female – 32:18) patients were included, with a mean age of 49.5 ± 7.8 years, mean BMI of 28.3 ± 3.4 kg/m2 and a mean 25(OH)D concentration of 18.5 ± 6.4 ng/ml. Mean systolic blood pressure (SBP) was 162.4 ± 20.2 mm Hg and mean diastolic blood pressure (DBP) was 100.2 ± 11.2 mm Hg. All the three blood pressure parameters [SBP, DBP and mean arterial pressure (MAP)] were significantly higher among individuals with lower 25(OH)D levels. The P values for trends in SBP, DBP and MAP were 0.009, 0.01 and 0.007, respectively. Though all the three blood pressure parameters (SBP, DBP and MAP) were higher among individuals with higher BMIs, they were not achieving statistical significance. Increasing trends in PRA and PAC were noticed with lower 25(OH)D and higher BMI levels.Conclusion:Vitamin D deficiency and obesity are associated with stimulation of RAAS activity. Vitamin D supplementation along with weight loss may be studied as a therapeutic strategy to reduce tissue RAS activity in individualswith Vitamin D deficiency and obesity.

Comparative analysis of telmisartan and olmesartan on cardiac function in the transgenic (mRen2)27 rat

Telmisartan, an angiotensin receptor blocker, may have unique benefits as it possesses partial peroxisome proliferator-activated receptor (PPAR)-γ agonist activity in addition to antihypertensive effects. In this study, we test whether treatment with telmisartan ameliorates cardiovascular abnormalities to a greater extent than olmesartan, which has little PPAR-γ activity. The hypertensive rodent model of tissue renin-angiotensin system activation, transgenic (mRen2)27 (Ren2) rats and their littermate Sprague-Dawley controls were used. Rats were treated with telmisartan (2 mg · kg(-1) · day(-1)), olmesartan (2.5 mg · kg(-1) · day(-1)), or vehicle via drinking water for 3 wk; these doses achieved similar blood pressure control, as measured by telemetry. Ren2 rats displayed impaired diastolic and systolic function using left ventricular (LV) pressure-volume (P-V) analysis. Load-independent diastolic indexes, including the time constant of isovolumic relaxation and the slope of the end-diastolic P-V relationship, as well as systolic indexes, including preload recruitable stroke work, the dP/dt(max)-end-diastolic volume (EDV) relationship, and the P-V area-EDV relationship, were elevated in Ren2 rats compared with Sprague-Dawley controls (P < 0.05). The Ren2 myocardium exhibited parallel increases in the oxidant markers NADPH oxidase and 3-nitrotyrosine. The increase in the prohypertrophic protein Jak2 in Ren2 rats was associated with cardiac structural abnormalities using light microscopic and ultrastructural analysis, which included interstitial fibrosis, cardiomyocyte and LV hypertrophy, and mitochondrial derangements. Both angiotensin receptor blockers attenuate these abnormalities to a similar extent. Our data suggest that the beneficial effect of telmisartan and olmesartan on cardiac structure and function may be predominantly pressor-related or angiotensin type 1 receptor dependent in this model of renin-angiotensin system activation.

Tumor necrosis factor-α: a reno-protective cytokine? Focus on “Tumor necrosis factor-α suppresses angiotensinogen expression through formation of a p50/p50 homodimer in human renal proximal tubular cells”

<i>Tumor necrosis factor-α: a reno-protective cytokine?</i> Focus on “Tumor necrosis factor-α suppresses angiotensinogen expression through formation of a p50/p50 homodimer in human renal proximal tubular cells”

A mechanism for salt-sensitive hypertension: abnormal dietary sodium-mediated vascular response to angiotensin-II

Several mechanisms have been proposed for salt-sensitive hypertension, with most focusing on impaired renal sodium handling. We tested the hypothesis that abnormalities in peripheral vascular responsiveness to angiotensin-II (ANGII) might also exist in salt-sensitive hypertension because of the interplay of the renin-angiotensin system and dietary sodium. Blood pressure (BP) response to ANGII infusion was studied in 295 hypertensive and 165 normotensive individuals after 7 days of high (200 mEq/day) and low (10 mEq/day) dietary sodium. Normotensive individuals demonstrated higher BP response to ANGII on high-salt than low-salt diet, whereas hypertensive individuals had similar responses on both diets; that is, the high-salt response was not enhanced as compared with low-salt response. Additionally, hypertensive individuals had a significantly greater high-salt BP response to norepinephrine than to ANGII. There was no correlation between the high-salt hormone levels and the difference in BP response to ANGII between the two diets. When stratified by BP response to dietary salt restriction, individuals with salt sensitivity of BP demonstrated abnormal high-salt BP responsiveness to ANGII. To assess if this represented increased tissue renin-angiotensin system activity in the vasculature, BP responses to angiotensin were compared before and after captopril in 20 hypertensive individuals on a high-salt diet. Individuals with the greatest BP-lowering effect to captopril had similar high and low-salt BP responses to ANGII at baseline and a significant increase in the high-salt response after captopril. Hypertensive individuals have an abnormal vascular response to ANGII infusion on a high-salt diet. Dysregulated tissue renin-angiotensin system activity may play a role in this abnormal response. These findings raise an intriguing novel possibility for the pathophysiologic mechanism of salt-sensitive hypertension.