Plasma Flow Response Research Articles

Striatin Gene Variants Are Associated With Salt Sensitivity of Blood Pressure by Mechanisms That Differ in Women and Men.

Salt sensitivity of blood pressure (SSBP) is a substantial risk factor for cardiovascular morbidity and mortality. Striatin (STRN) is critical for estrogen and aldosterone nongenomic signaling. However, the role of biological sex on the SSBP phenotype associated with STRN gene variants remains unexplored. Data from 1306 subjects participating in the Hypertensive Pathotype (HyperPATH) Consortium were used to identify STRN gene single-nucleotide variants associated with SSBP. Haploblock analysis revealed a novel diplotype in the upstream regulatory region of STRN (rs888083 and rs6744560), with 31% of subjects being homozygous for the risk diplotype. Individuals homozygous for the risk diplotype had significantly greater SSBP than nonrisk diplotypes (P<0.009). While a significant genotype/SSBP association was present in both sexes, their potential mechanisms differed. Women, but not men homozygous risk diplotypes, had significantly greater aldosterone levels than nonrisk diplotypes (5.8±0.4 versus 3.2±0.7 ng/dl; P=0.01; liberal Na+ diet, adjusted). Men, but not women, homozygous risk diplotypes, had significantly reduced renal plasma flow response to Angiotensin II than nonrisk diplotypes (delta 95.2±5.2 versus 122.9±10.2 mL/min per 1.73 m2; P=0.01; liberal Na+ diet, adjusted). The single-nucleotide variants composing the risk diplotype were associated with lower STRN mRNA expression in human tissues (in silico). In women, the primary driver of SSBP is increased aldosterone, while in men, it is reduced renal plasma flow responses. Thus, despite a common hypertensive phenotype (SSBP) in both sexes, the specific treatment approaches might differ to increase therapeutic gain and mitigate adverse effects. These genetic- and sex-based observational results require confirmation in a prospective clinical study.

Analytical model for quasi-linear flow response to resonant magnetic perturbation in resistive-inertial and viscous-resistive regimes

In this work, a quasi-linear model for the plasma flow response to the resonant magnetic perturbation (RMP) in a tokamak has been self-consistently developed in the resistive-inertial and viscous-resistive regimes purely from the two-field reduced MHD model. Models for the plasma response to RMP are commonly composed of equations for the resonant magnetic field response (i.e., the magnetic island) and the torque balance of plasma flow. However, in previous plasma response models, the magnetic island and the torque balance equations are often derived separately from reduced MHD and full MHD equations, respectively. By contrast, in this work, we derive both the magnetic island response and the torque balance equations in a quasi-linear model for the plasma flow response entirely from a set of two-field reduced MHD equations. Such a quasi-linear model can recover previous plasma flow response models within certain limits and approximations. Furthermore, the theoretical origins and physical meanings of quasi-linear forces and moments in the flow response equation are also clarified.

Renal and Vascular Effects of Uric Acid Lowering in Normouricemic Patients With Uncomplicated Type 1 Diabetes.

Higher plasma uric acid (PUA) levels are associated with lower glomerular filtration rate (GFR) and higher blood pressure (BP) in patients with type 1 diabetes (T1D). Our aim was to determine the impact of PUA lowering on renal and vascular function in patients with uncomplicated T1D. T1D patients (n = 49) were studied under euglycemic and hyperglycemic conditions at baseline and after PUA lowering with febuxostat (FBX) for 8 weeks. Healthy control subjects were studied under normoglycemic conditions (n = 24). PUA, GFR (inulin), effective renal plasma flow (para-aminohippurate), BP, and hemodynamic responses to an infusion of angiotensin II (assessment of intrarenal renin-angiotensin-aldosterone system [RAAS]) were measured before and after FBX treatment. Arterial stiffness, flow-mediated dilation (FMD), nitroglycerin-mediated dilation (GMD), urinary nitric oxide (NO), and inflammatory markers were measured before and after FBX treatment. Gomez equations were used to estimate arteriolar afferent resistance, efferent resistance (RE), and glomerular hydrostatic pressure (PGLO). FBX had a modest systolic BP-lowering effect in T1D patients (112 ± 10 to 109 ± 9 mmHg, P = 0.049) without impacting arterial stiffness, FMD, GMD, or NO. FBX enhanced the filtration fraction response to hyperglycemia in T1D patients through larger increases in RE, PGLO, and interleukin-18 but without impacting the RAAS. FBX lowered systolic BP and modulated the renal RE responses to hyperglycemia but without impacting the RAAS or NO levels, suggesting that PUA may augment other hemodynamic or inflammatory mechanisms that control the renal response to hyperglycemia at the efferent arteriole. Ongoing outcome trials will determine cardiorenal outcomes of PUA lowering in patients with T1D.

The effect of vitamin D on renin-angiotensin system activation and blood pressure: a randomized control trial.

Disruption of vitamin D signaling in rodents causes activation of the rennin-angiotensin system (RAS) and development of hypertension. Observational studies in humans found lower circulating 25-hydroxyvitamin D [25(OH)D] is associated with increased RAS activity and blood pressure (BP). We performed the first randomized control trial to investigate the effects of vitamin D supplementation on the RAS in humans. Vitamin D deficient, [25(OH)D ≤20 ng/ml), overweight individuals without hypertension were randomized into a double-blind, placebo-controlled trial of 8-weeks treatment with ergocalciferol or placebo. Kidney-specific RAS activity, measured using renal plasma flow response to captopril in high sodium balance, was assessed at baseline and 8 weeks, as was systemic RAS activity and 24-h ambulatory BP. In total, 84 participants completed the study. Mean 25[OH]D levels increased from 14.7 to 30.3 ng/ml in the ergocalciferol group, P value < 0.0001, and from 14.3 to 17.4 ng/ml in the placebo group, P value = 0.3. The renal plasma flow response to captopril was 33.9 ± 56.1 ml/min per 1.73 m at baseline and 35.7 ± 47.7 ml/min per 1.73 m at 8 weeks in the ergocalciferol group (P value = 0.83); and was 37.3 ± 46.9 ml/min per 1.73 m at baseline and 35.9 ± 26.2 ml/min per 1.73 m at 8 weeks in the placebo group (P value = 0.78). Ergocalciferol had no effect on PRA, AngII, or 24-h BP measurements. This trial found no benefit from correcting vitamin D deficiency on RAS activity or BP after 8 weeks. These findings are not consistent with the hypothesis that vitamin D is a modifiable target for lowering BP in vitamin D deficient individuals.

Effect of Uric Acid Lowering on Renin-Angiotensin-System Activation and Ambulatory BP: A Randomized Controlled Trial.

Higher serum uric acid levels, even within the reference range, are strongly associated with increased activity of the renin-angiotensin system (RAS) and risk of incident hypertension. However, the effect of lowering serum uric acid on RAS activity in humans is unknown, although the data that lowering serum uric acid can reduce BP are conflicting. In a double-blind placebo-controlled trial conducted from 2011 to 2015, we randomly assigned 149 overweight or obese adults with serum uric acid ≥5.0 mg/dl to uric acid lowering with either probenecid or allopurinol, or to placebo. The primary endpoints were kidney-specific and systemic RAS activity. Secondary endpoints included mean 24-hour systolic BP, mean awake and asleep BP, and nocturnal dipping. Allopurinol and probenecid markedly lowered serum uric acid after 4 and 8 weeks compared with placebo (mean serum uric acid in allopurinol, probenecid, and placebo at 8 weeks was 2.9, 3.5, and 5.6 mg/dl, respectively). The change in kidney-specific RAS activity, measured as change in the median (interquartile range) renal plasma flow response to captopril (in ml/min per 1.73 m2) from baseline to 8 weeks, was -4 (-25 to 32) in the probenecid group (P=0.83), -4 (-16 to 9) in the allopurinol group (P=0.32), and 1 (-21 to 17) in the placebo group (P=0.96), with no significant treatment effect (P=0.77). Similarly, plasma renin activity and plasma angiotensin II levels did not significantly change with treatment. The change in mean (±SD) 24-hour systolic BPs from baseline to 8 weeks was -1.6±10.1 with probenecid (P=0.43), -0.4±6.1 with allopurinol (P=0.76), and 0.5±6.0 with placebo (P=0.65); there was no significant treatment effect (P=0.58). Adverse events occurred in 9%, 12%, and 2% of those given probenecid, allopurinol, or placebo, respectively. In contrast to animal experiments and observational studies, this randomized, placebo-controlled trial found that uric acid lowering had no effect on kidney-specific or systemic RAS activity after 8 weeks or on mean systolic BP. These data do not support the hypothesis that higher levels of uric acid are a reversible risk factor for increased BP.

Monosodium glutamate intake affect the function of the kidney through NMDA receptor

AimsWe investigated whether the chronic intake of monosodium glutamate (MSG) with food affects kidney function, and renal response to glycine. We also established if the NMDA receptors are involved in the changes observed. Main methodsMale Wistar rats (5weeks old) were fed a diet supplemented with MSG (3g/kg b.w./day), five days a week, and spontaneous ingestion of a 1% MSG solution during 16weeks. NaCl rats were fed a diet with NaCl (1g/kg b.w./day) and 0.35% NaCl solution at the same frequency and time. Control group was fed with normal chow and tap water. We utilized clearance techniques to examine glomerular filtration rate (GFR) and cortical renal plasma flow (CRPF) response to glycine and glycine+MK-801 (antagonist NMDA-R), and we determined NMDA-R1 in kidney by immunohistochemistry. Key findingsThe addition of MSG in the diet of rats increased both GFR and CRPF with an increase of absolute sodium reabsorption. However, hyperfiltration was accompanied with a normal response to glycine infusion. Immunostain of kidney demonstrate that the NMDA receptor is upregulated in rats fed with MSG diet. NMDA-R antagonist MK-801 significantly reduced both the GFR and CRPF; however the percentage of reduction was significantly higher in the group MSG. MK-801 also reduces fractional excretion of water, sodium and potassium in the three groups. SignificanceRenal NMDAR may be conditioned by the addition of MSG in the diet, favoring the hyperfiltration and simultaneously Na retention in the body.

Full kinetic simulations of plasma flow interactions with meso- and microscale magnetic dipoles

We examined the plasma flow response to meso- and microscale magnetic dipoles by performing three-dimensional full particle-in-cell simulations. We particularly focused on the formation of a magnetosphere and its dependence on the intensity of the magnetic moment. The size of a magnetic dipole immersed in a plasma flow can be characterized by a distance L from the dipole center to the position where the pressure of the local magnetic field becomes equal to the dynamic pressure of the plasma flow under the magnetohydrodynamics (MHD) approximation. In this study, we are interested in a magnetic dipole whose L is smaller than the Larmor radius of ions riL calculated with the unperturbed dipole field at the distance L from the center. In the simulation results, we confirmed the clear formation of a magnetosphere consisting of a magnetopause and a tail region in the density profile, although the spatial scale is much smaller than the MHD scale. One of the important findings in this study is that the spatial profiles of the plasma density as well as the current flows are remarkably affected by the finite Larmor radius effect of the plasma flow, which is different from the Earth's magnetosphere. The magnetopause found in the upstream region is located at a position much closer to the dipole center than L. In the equatorial plane, we also found an asymmetric density profile with respect to the plasma flow direction, which is caused by plasma gyration in the dipole field region. The ion current layers are created in the inner region of the dipole field, and the electron current also flows in the region beyond the ion current layer because ions with a large inertia can closely approach the dipole center. Unlike the ring current structure of the Earth's magnetosphere, the current layers in the microscale dipole fields are not circularly closed around the dipole center. Since the major current is caused by the particle gyrations, the current is independently determined to be in the direction of the electron and ion gyrations, which are the same in both the upstream and downstream regions. The present analysis on the formation of a magnetosphere in the regime of a microscale magnetic dipole is significant for understanding the solar wind response to the crustal magnetic anomalies on the Moon surface, such as were recently observed by spacecraft.

Renal responses to furosemide are significantly attenuated in male sheep at 6 months of age following fetal uninephrectomy

We have previously shown that fetal uninephrectomy (uni-x) at 100 days of gestation (term = 150 days) in male sheep results in a 30% nephron deficit, reduction in glomerular filtration rate (GFR) and renal blood flow, and elevation in arterial pressure at 6 mo of age. Furthermore, in response to an acute 0.9% saline load, sodium excretion was significantly delayed in uni-x animals leading us to speculate that tubuloglomerular feedback (TGF) activity was reset in uni-x animals. In the present study, we induced TGF blockade by furosemide administration (1.5 mg/kg iv over 90 min) and determined GFR, effective renal plasma flow, and urine and sodium excretion responses in 6-mo-old male sheep. In response to furosemide, a significant diuresis and natriuresis was observed in the sham group; however, the response was significantly delayed and reduced in uni-x animals (both, P(treatment×time) < 0.001). Cummulative urinary and sodium output was significantly less in the uni-x compared with the sham sheep (both, P(treatment×time) < 0.001). GFR was increased in the sham but not the uni-x sheep (P(treatment×time) < 0.0001). In conclusion, the excretory response to furosemide was attenuated in the uni-x sheep, and this suggests a rightward resetting of the TGF operating point. The TGF mechanism is important in the fine tuning of sodium homeostasis and is likely a contributing factor for the dysfunction in sodium regulation we have previously observed in the uni-x animals.

The nonlinear coupling between gyroradius scale turbulence and mesoscale magnetic islands in fusion plasmas

The interaction between small scale turbulence (of the order of the ion Larmor radius) and mesoscale magnetic islands is investigated within the gyrokinetic framework. Turbulence, driven by background temperature and density gradients, over nonlinear mode coupling, pumps energy into long wavelength modes, and can result in an electrostatic vortex mode that coincides with the magnetic island. The strength of the vortex is strongly enhanced by the modified plasma flow response connected with the change in topology, and the transport it generates can compete with the parallel motion along the perturbed magnetic field. Despite the stabilizing effect of sheared plasma flows in and around the island, the net effect of the island is a degradation of the confinement. When density and temperature gradients inside the island are below the threshold for turbulence generation, turbulent fluctuations still persist through turbulence convection and spreading. The latter mechanisms then generate a finite transport flux and, consequently, a finite pressure gradient in the island. A finite radial temperature gradient inside the island is also shown to persist due to the trapped particles, which do not move along the field around the island. In the low collisionality regime, the finite gradient in the trapped population leads to the generation of a bootstrap current, which reduces the neoclassical drive.

Plasma 25-Hydroxyvitamin D and Regulation of the Renin-Angiotensin System in Humans

Vitamin D regulates the renin-angiotensin system (RAS) in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the RAS in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II (Ang II) and the renal plasma flow response to infused Ang II, which is an indirect measure of the intrinsic RAS activity in the kidney. Compared with individuals with sufficient 25-hydroxyvitamin D levels (> or = 30.0 ng/mL), those with insufficiency (15.0 to 29.9 ng/mL) and deficiency (<15.0 ng/mL) had higher circulating Ang II levels (P for trend=0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused Ang II (mean decrease of 115 mL/min per 1.73 m(2) in renal plasma flow versus 145 mL/min per 1.73 m(2) among those with sufficient vitamin D levels; P for trend=0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy humans.

Angiotensinogen genotype predicts abnormal renal hemodynamics in young hypertensive patients

In essential hypertensive patients, blunted renal plasma flow responsiveness to angiotensin II suggests a pathologic increase in angiotensin II in the kidneys. This blunting has been associated with the angiotensinogen 235TT genotype. As several measures of renal function decline with age, we sought to determine the interaction of age and genotype on this intermediate phenotype. Three hundred fifteen participants had renal plasma flow response to subpressor doses of angiotensin II (3 ng/kg/min) measured by para-aminohippuric acid clearance in high-sodium balance. Individuals were divided by median age into young (<45 years) and older (> or =45 years) sets. A subset of participants was also studied after administration of captopril. Age, baseline renal plasma flow, BMI and angiotensinogen 235 genotype independently predicted renal plasma flow responsiveness to angiotensin II. Renal plasma flow responses were lower in older individuals than younger (P = 0.03, hypertensive patients; P = 0.004, normotensive individuals). Both hypertensive patients and normotensive individuals carrying either angiotensinogen 235MM or MT genotypes showed this inverse association (P = 0.005, hypertensive patients; P = 0.05, normotensive individuals). However, among angiotensinogen 235TT homozygotes the pattern differed: normotensive individuals had a fall in renal vascular responsiveness with age (P = 0.01) but hypertensive patients did not (P = 0.72). Young hypertensive patients already showed blunted responses. Of all genotype subsets, only angiotensinogen 235TT hypertensive patients showed enhancement (P = 0.03) of the renal vascular responsiveness to angiotensin II after captopril. The angiotensinogen 235TT variant predicts premature blunting of renal vascular responsiveness among young hypertensive patients. This abnormal response is corrected by angiotensin-converting enzyme inhibition. This first report of age and genotype interaction may have important implications in the profiling and management of essential hypertension.

Renal and Hormonal Responses to Direct Renin Inhibition With Aliskiren in Healthy Humans

Pharmacological interruption of the renin-angiotensin system focuses on optimization of blockade. As a measure of intrarenal renin activity, we have examined renal plasma flow (RPF) responses in a standardized protocol. Compared with responses with angiotensin-converting enzyme inhibition (rise in RPF approximately 95 mL x min(-1) x 1.73 m(-2)), greater renal vasodilation with angiotensin receptor blockers (approximately 145 mL x min(-1) x 1.73 m(-2)) suggested more effective blockade. We predicted that blockade with the direct oral renin inhibitor aliskiren would produce renal vascular responses exceeding those induced by angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Twenty healthy normotensive subjects were studied on a low-sodium (10 mmol/d) diet, receiving separate escalating doses of aliskiren. Six additional subjects received captopril 25 mg as a low-sodium comparison and also received aliskiren on a high-sodium (200 mmol/d) diet. RPF was measured by clearance of para-aminohippurate. Aliskiren induced a remarkable dose-related renal vasodilation in low-sodium balance. The RPF response was maximal at the 600-mg dose (197+/-27 mL x min(-1) x 1.73 m(-2)) and exceeded responses to captopril (92+/-20 mL x min(-1) x 1.73 m(-2); P<0.01). Furthermore, significant residual vasodilation was observed 48 hours after each dose (P<0.01). The RPF response on a high-sodium diet was also higher than expected (47+/-17 mL x min(-1) x 1.73 m(-2)). Plasma renin activity and angiotensin levels were reduced in a dose-related manner. As another functional index of the effect of aliskiren, we found significant natriuresis on both diets. Renal vasodilation in healthy people with the potent renin inhibitor aliskiren exceeded responses seen previously with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects were longer lasting and were associated with significant natriuresis. These results indicate that aliskiren may provide more complete and thus more effective blockade of the renin-angiotensin system.

Gender and the Renal Nitric Oxide Synthase System in Healthy Humans

It is widely known that men with kidney disease progress to ESRD at a much greater rate than do women. The mechanism for these gender differences is not clear, but reduced availability of nitric oxide is thought to contribute to the age-related decline in renal plasma flow observed in both healthy men and women. Animal models suggest that the renal vasculature of men may be significantly more dependent on nitric oxide than that of women. Renal plasma flow response to the nonspecific nitric oxide synthase inhibitor nitro-L-arginine methyl ester (L-NAME) was measured by para-aminohippurate clearance technique in 21 healthy, normotensive (8 male, 13 female) individuals in balance on a high-salt diet. There were striking differences between the genders in the renal hemodynamic response to L-NAME according to age, a difference that remained even after adjustment for other significant covariates. In men, the fall in renal plasma flow induced by L-NAME increased remarkably with increasing age. In women, there was no influence of age on the renovascular response to L-NAME. Neither age nor gender predicted the mean arterial pressure response to L-NAME. The renal vasculature of men becomes more dependent on nitric oxide with age compared with that of women, suggesting that any renal disease that interferes with nitric oxide production may, over time, cause existent kidney damage to progress more quickly in men relative to women.

Racial differences in renal vascular response to angiotensin blockade with captopril or candesartan

We compared the renal vascular response to captopril and candesartan among nondiabetic, normotensive black and white participants to explore angiotensin-converting enzyme-independent generation of angiotensin II. Thirteen black individuals and 10 white individuals in low-salt balance were given captopril and candesartan on sequential study days, and the renal plasma flow responses to these agents were measured. Consistent with our prior observations, white individuals demonstrated a strong, significant correlation between responses to these drugs (r = 0.78, P = 0.008) and a significantly greater increase in the renal plasma flow in response to candesartan compared with captopril (104.2 +/- 26.8 versus 52.4 +/- 24.3 ml/min per 1.73 m; P = 0.03). In black participants, however, no correlation between responses to captopril and to candesartan was observed (r = 0.22, P = 0.47) and there was no difference in the renal plasma flow response between the two drugs (90.4 +/- 13.0 versus 80.4 +/- 15.3 ml/min per 1.73 m; P = 0.59). The difference in the response to the two drugs was significantly higher among white participants compared with black participants (P = 0.03). We confirmed the contribution of an angiotensin-converting enzyme-independent pathway for angiotensin II generation in the kidneys of nondiabetic, normotensive white, but not black, individuals.

Body Mass Index and Angiotensin-Dependent Control of the Renal Circulation in Healthy Humans

Obesity is increasingly recognized as a risk factor for renal disease, but the mechanism is unclear. Renal plasma flow response to captopril, as an index of renin-angiotensin system activity, was measured by para-aminohippurate clearance technique in 100 healthy, normotensive subjects in balance on a high-salt diet. Of the 100 subjects, body mass index exceeded 25 in 56 and exceeded 30 in 22. The average vasodilator response to captopril was 27+/-7 mL/min per 1.73 m2 (P<0.0001). After adjustment for other predictors of the renal plasma flow response to captopril using a multivariate linear regression model, there was a highly significant relationship between age- and plasma renin activity-adjusted body mass index and the renal plasma flow response to captopril; however, a quadratic model provided a substantially better fit (r=0.55; P<0.0001; P=0.03 versus linear correlation). The strong association between increasing body mass index and angiotensin-dependent control of the renal circulation suggests that this may be a mechanism by which obesity contributes to renal disease. Weight loss should be considered in the overweight or obese patient for renal protection.

Oral Contraceptives, Angiotensin-Dependent Renal Vasoconstriction, and Risk of Diabetic Nephropathy

Diabetes, the leading cause of end-stage renal disease in the U.S., is believed to involve activation of the renin angiotensin system (RAS) as a risk factor for nephropathy. RAS activation occurs in healthy women using oral contraceptives (OCs), but the effects of OC use on the diabetic kidney are unclear. Renal plasma flow (RPF) response to captopril, as an index of RAS activity, was investigated in 92 women (41 nondiabetic OC nonusers, 10 nondiabetic OC users, 29 diabetic OC nonusers, and 12 diabetic OC users). Based on the hemodynamic findings, we examined the impact of OC use on the development of nephropathy as a post hoc analysis in an inception cohort of 114 female patients with newly diagnosed type 1 diabetes followed for a median of 20.7 years (range 1-24). Nondiabetic OC nonusers showed minimal RPF vasodilator response to captopril (9 +/- 10 ml x min(-1) x 1.73 m(-2), P = 0.6). In comparison, nondiabetic OC users showed a significant increase (69 +/- 35 ml x min(-1) x 1.73 m(-2), P = 0.02) (P = 0.04 vs. nondiabetic OC nonusers). Diabetic OC nonusers demonstrated the anticipated vasodilator response (58 +/- 12 ml x min(-1) x 1.73 m(-2), P < 0.0001). Diabetic OC users showed the largest responses (84 +/- 12 ml x min(-1) x 1.73 m(-2), P = 0.002) (P = 0.04 vs. diabetic OC nonusers). Plasma renin activity did not vary with OC use (P = 0.3). The RPF responses to captopril and angiotensin receptor blocker were highly correlated (r = 0.72, P < 0.001), suggesting clear involvement of the RAS. In the observational study, 18% (6/33 [95% CI 4.3-32.1]) of OC users developed macroalbuminuria compared with 2% (2/81 [0-5.9]) of OC nonusers (P = 0.003, univariate analysis). After adjustment for known risk factors with a Cox regression model, OC use remained a predictor for the development of macroalbuminuria (relative risk 8.90 [95%CI 1.79-44.36], P = 0.008). The strong association of OC use with angiotensin-dependent control of the renal circulation and the development of macroalbuminuria suggest that OC use may be a risk factor for diabetic nephropathy. Large prospective studies are required to further investigate this relationship.

Uric acid and the state of the intrarenal renin-angiotensin system in humans

Experimental hyperuricemia is marked by an activated intrarenal renin-angiotensin system (RAS). The renal vascular response to exogenous angiotensin II (Ang II) provides an indirect measure of intrarenal RAS activity. We tested the hypothesis that the serum uric acid concentration predicts the renal vascular response to Ang II. A total of 249 subjects in high sodium balance had the renal plasma flow (RPF) response to Ang II measured. Para-aminohippuric acid (PAH) clearance was used to estimate RPF. Multivariable regression analysis determined if the serum uric acid concentration independently predicts the RPF response to Ang II. Variables considered included age, gender, race, body mass index (BMI), hypertension status, blood pressure, basal RPF, creatinine clearance, serum insulin, serum glucose, serum high-density lipoprotein (HDL), serum triglycerides, and plasma renin activity (PRA). Uric acid concentration negatively correlated with the RPF response to Ang II (r=-0.37, P < 0.001). In univariate analysis, age, BMI, hypertension, triglycerides, and blood pressure were negatively associated, and basal RPF, HDL, and female gender were positively associated with the RPF response to Ang II. In multivariable analysis, serum uric acid concentration independently predicted the RPF response to Ang II (beta=-5.3, P < 0.001). Serum uric acid independently predicted blunted renal vascular responsiveness to Ang II, consistent with results from experimental hyperuricemia showing an activated intrarenal RAS. This could be due to a direct effect of uric acid or reflect a more fundamental renal process. These data may have relevance to the association of uric acid with risk for hypertension and nephropathy.

Genes, Environment, Intermediate Phenotypes, and the Pathogenesis of Diabetic Nephropathy

The potential of pharmacogenomics has received widespread attention. The goals include identifying patients in whom a substantial response, or the absence of a response, to an individual drug can be anticipated; targets for drug therapy based on genetic polymorphisms involved in pathogenesis; and new opportunities for drug development. Diabetic (DM) nephropathy provides a useful model for exploring these issues since nephropathy occurs in 30-40% of patients, and diabetes is the most common cause of end-stage renal disease. Hyperglycemia and hypertension clearly contribute but do not explain fully the development of DM nephropathy. Family studies showed familial clustering in both type 1 and type 2 DM, with about a 3-fold increased risk in siblings if the proband had DM nephropathy. A search for candidate genes followed. The effectiveness of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers in delaying the progression of DM nephropathy led to studies centering on polymorphisms of genes involving the renin-angiotensin system. These include the ACE, AGT, AT1R and renin genes. Despite an enormous number of studies, the results are still equivocal. An alternative approach is to use an intermediate phenotype to explore mechanisms. Our efforts have involved assessing the renal plasma flow response to ACE inhibition and angiotensin II receptor blockade in DM as an intermediate phenotype. The response provides a measure of angiotensin-dependent renal vasoconstriction, and thus, an index of intrarenal renin-angiotensin system activation, and shows promise as an effective tool in exploring the relation between gene polymorphisms and risk of disease. Keywords: pharmacogenomics, renin-angiotensin, angiotensin, vasoconstriction

Role of reactive oxygen species in endothelin-induced hypertension.

Recent reports have indicated that endothelin-induced vasoconstriction in isolated aortic vascular rings may be mediated by the production of superoxide anion. The purpose of this study was to determine the role of superoxide anion in mediating the chronic renal and hypertensive actions of endothelin. Endothelin-1 (5 pmol/kg per minute) was chronically infused into the jugular vein by use of mini-osmotic pump for 9 days in male Sprague-Dawley rats and in rats treated with the superoxide anion scavenger tempol (30 mg/kg per day). Mean arterial pressure in the endothelin-1-treated rats was 141+/-3 mm Hg, compared with 125+/-2 mm Hg in control rats. Endothelin-1 increased renal vascular resistance (15.3+/-2.5 versus 10+/-1.3 mm Hg/mL per minute) and decreased renal plasma flow (6.5+/-0.9 versus 8.7+/-0.7 mL/min) in control rats. Endothelin-1 also significantly increased TBARS in the kidney and urinary 8-isoprostaglandin F2alpha excretion. The increase in arterial pressure in response to endothelin-1 was completely abolished by tempol (127+/-4 versus 127+/-4 mm Hg). Tempol also markedly attenuated the renal plasma flow and renal vascular resistance response to endothelin-1. Tempol also significantly decreased the level of 8-isoprostaglandin F2alpha in the endothelin-1-treated rats. Tempol had no effect on arterial pressure or renal hemodynamics in control rats. These data indicate that formation of reactive oxygen species may play an important role in mediating hypertension induced by chronic elevations in endothelin.

Type 2 diabetes, obesity, and the renal response to blocking the renin system with irbesartan.

Our recent studies revealed a striking but variable enhancement of renal vasodilator responses to blockers of the renin-angiotensin system in subjects with diabetes mellitus, possibly reflecting the level of intrarenal activation of the renin-angiotensin system, and thus a risk of nephropathy. As obesity is a common finding in diabetic individuals, and obesity has been linked to an increase in plasma angiotensinogen levels, we enrolled diabetic subjects with a wide range of body mass index (BMI) for this study. Twelve Type 2 diabetic subjects in balance on a low sodium diet participated after baseline renal plasma flow and glomerular filtration measurements were made. Each subject then received 150 mg irbesartan, and renal function was measured every 45 min for 4 h. The average vasodilator response to irbesartan was 174 +/- 33 ml/min. No correlation was found between renal plasma flow response to irbesartan and duration of diabetes, baseline glucose, or HbA1c level. BMI, our measure of obesity, was highly correlated to the renal response to irbesartan (r = 0.7; P = 0.01). Our findings suggest an important role for obesity in activating the intrarenal renin system, perhaps via production of angiotensinogen. BMI may be an indicator of risk of nephropathy.