Effects Of Sodium-restricted Diet Research Articles

MO068: Paraoxonase 2 Protects the Kidney Tissue from Aldosterone-Promoted Oxidative Stress in Milan Normotensive Rats Strain

Abstract BACKGROUND AND AIMS Kidney plays a pivotal role on the maintenance of blood pressure by the regulation of sodium reabsorption. Aldosterone sensitive distal nephron finely tunes salt reabsorption through several transporters, including the epithelial sodium channel (ENaC). Alteration in ENaC function leads to clinical relevant conditions associated with high or low blood pressure when gain or loss of function mutations occur, respectively. Recently, accumulating evidence suggests the putative role of renal Paraoxonase 2 (PON2) as regulator of ENaC function. PON2 is a membrane-associated enzyme showing hydrolytic activity against 3-oxo-C12 homoserine lactone, a signaling molecule produced by bacteria and mainly Pseudomonas aeruginosa. PON2 also exhibits antioxidant property. In the distal nephron, PON2 is expressed in principal cells, and in vitro it physically interacts with ENaC subunits and inhibits ENaC channel activity in Xenopus oocytes likely by modulating channel assembly in the endoplasmic reticulum. However, the role of PON2 in the kidney is still not known. In the present study, we investigate whether PON2 is regulated by changes in aldosterone state and its role in aldosterone-induced oxidative stress in the kidneys. METHOD We addressed these issues utilizing both in vivo and in vitro approaches, such as RESULTS We first demonstrated that in Milan normotensive rats strain, PON2 is upregulated by low-salt state according with α-ENaC activation. This regulation is aldosterone sensitive since pretreatment with mineralocorticoid receptor antagonist spironolactone prevented the stimulatory effects of sodium restricted diet. Furthermore, low-sodium diet inducing PON2 upregulation was associated with reduced ROS levels, more specifically superoxide levels, but treatment with spironolactone prevented this beneficial effect, by increasing ROS level in kidney cortex. Since antihypertensive drugs spironolactone and canrenone contain a lactone residue in their molecular structure, we tested whether they could directly interact with PON2. We demonstrated in vitro that spironolactone and canrenone were able to inhibit PON2 lactonase activity and so to directly interfere with PON2 function. Finally, Milan hypertensive rats, carrying a mutation of α-adducin as determinant of their hypertensive phenotype, presented with higher level of ROS while PON2 was upregulated. CONCLUSION These results demonstrate PON2 as a novel target of steroid hormone aldosterone. PON2 may serve as a potential ROS scavenger mechanism protecting the kidneys from aldosterone-promoted oxidative stress.

A Randomized Crossover Trial of Dietary Sodium Restriction in Stage 3-4 CKD.

Patients with chronic kidney disease (CKD) are often volume expanded and hypertensive. Few controlled studies have assessed the effects of a sodium-restricted diet (SRD) in CKD. We conducted a randomized crossover trial to evaluate the effect of SRD (target <2 g sodium per day) versus usual diet on hydration status (by bioelectrical impedance spectroscopy) and blood pressure (BP) between May of 2009 and May of 2013. A total of 58 adults with stage 3-4 CKD were enrolled from two academic sites: University of Michigan (n=37) and University of North Carolina at Chapel Hill (n=21); 60% were men, 43% were diabetic, 93% were hypertensive, and mean age was 61 years. Participants followed SRD or usual diet for 4 weeks, followed by a 2-week washout period and a 4-week crossover phase. During the SRD, dieticians provided counseling every 2 weeks, using motivational interviewing techniques. Whole-body extracellular volume and calf intracellular volume decreased by 1.02 L (95% confidence interval [95% CI], -1.48 to -0.56; P<0.001) and -0.06 L (95% CI, -0.12 to -0.01; P=0.02), respectively, implying decreased fluid content on the SRD compared with usual diet. Significant reductions in urinary sodium (-57.3 mEq/24 h; 95% CI, -81.8 to -32.9), weight (-2.3 kg; 95% CI, -3.2 to -1.5), and 24-hour systolic BP (-10.8 mmHg; 95% CI, -17.0 to -4.6) were also observed (all P<0.01). Albumin-to-creatinine ratio did not change significantly and mean serum creatinine increased slightly (0.1 mg/dl; 95% CI, -0.01 to 0.2; P=0.06). No period or carryover effects were observed. Results were similar when analyzed from phase 1 only before crossover, although P values were modestly larger because of the loss of power. In this randomized crossover trial, implementation of SRD in patients with CKD stage 3-4 resulted in clinically and statistically significant improvement in BP and hydration status. This simple dietary intervention merits a larger trial in CKD to evaluate effects on major clinical outcomes.

The Effect of Sodium Restricted Diet on Plasma Visfatin Levels in Hypertensive Patients with Visceral Obesity

Aim/Background: Experimental and clinical studies revealed contradictory data concerning the influence of renin-angiotensin-aldosterone (RAA) system activation on visfatin release. The aim of the present study was the assessment of the effect of dietary sodium restriction with RAA system activation on visfatin level in hypertensive and normotensive patients with visceral obesity. Methods: The study included 24 hypertensive patients with visceral obesity (12 women) and 22 normotensive subjects with visceral obesity (11 women) constituting the control group. Plasma renin activity, plasma insulin, aldosterone and visfatin levels were determined twice, on normal-salt diet after 6-8 h in recumbent position and the second time after 3 days of dietary sodium restriction and upright position for 2 h. Dietary compliance was controlled by 24 h natriuresis measurement. Results: Hypertensive patients had significantly higher plasma visfatin level than the control group [11.0 (8.5-13.5) vs. 6.8 (6.0-7.6) ng/ml, p=0.003]. Dietary sodium restriction and upright position caused significant increase in PRA and plasma aldosterone level in both groups. While, plasma visfatin level remained unaffected. In the combined group plasma visfatin levels correlated with BMI (r=0.398), waist circumference (r=0.391), glucose (r=0.328), insulin (r=0.663), HOMA-IR (r=0.698), triglycerides (r=0.500) and CRP (r=0.546) but not with percentage of fat mass, percentage of trunk fat, and blood pressure values. Conclusions: 1) Increased plasma visfatin concentration may play a significant role in the pathogenesis of hypertension in patients with visceral obesity. 2) RAA system activation by dietary sodium restriction and upright position has no effect on plasma visfatin levels in subjects with visceral obesity.

Effect of sodium-restricted diet and posture on norepinephrine kinetics in humans.

We used compartmental analysis to analyze the kinetics of distribution and metabolism of norepinephrine (NE) and to determine whether the increase in plasma norepinephrine concentration (PNE) during sodium restriction in humans is due to sympathetic nervous system (SNS) activation. [3H]-NE infusion and postinfusion decay were measured in young subjects in the supine position and during 60 min of standing during normal sodium (NS) diet and after 7 days of 10 meq/day sodium-restricted (SR) diet. The mean supine PNE was greater during SR diet compared with NS diet (154 +/- 9 vs. 185 +/- 12 pg/ml, P = 0.02, n = 10). During both NS and SR diets, upright PNE increased (163 +/- 4 vs. 359 +/- 38 pg/ml and 182 +/- 8 vs. 401 +/- 26 pg/ml, respectively, multivariate one-way analysis of variance, P less than 0.001, alpha = 0.05). The increases of PNE with both SR diet and upright posture were accompanied by a fall in NE metabolic clearance rate (MCR1). During SR diet this was due to a fall in the volume of distribution of NE (6.1 +/- 0.4 vs. 5.0 +/- 0.4 liters, P = 0.003, n = 10). In contrast to the effect of upright posture to increase NE release into the extra-vascular compartment (NE2), during SR diet there was no change in NE2 (1.63 +/- 0.09 vs. 1.62 +/- 0.1 micrograms.min-1.m-2, P = 0.97, n = 10). Thus the increase in PNE during SR diet in humans can be explained by a fall in the volume of distribution of NE, resulting in a decrease in MCR1.(ABSTRACT TRUNCATED AT 250 WORDS)