Changes In Renal Sodium Handling Research Articles

Abstract P378: Impaired Diurnal Control of Blood Pressure and Sodium Excretion in Aged Hypertensive Male Sprague Dawley Rats

Hypothesis: The diurnal rhythmicity of blood pressure (BP) and sodium excretion is important to blood pressure regulation and is strongly influenced by the circadian clock genes. We hypothesized that the diurnal control of BP and natriuresis is impaired in aged male Sprague Dawley (SD) rats and may be associated with altered kidney expression of circadian clock gene proteins. Methods: Radiotelemetry (to record mean arterial BP (MAP)) and metabolic balance (to assess sodium excretion) was conducted in 3-month-old (3M) and 16-month-old (16M) male SD rats. On a separate day, 3M and 16M rats received an acute 900 μEq NaCl load by oral gavage at ZT0 and sodium excretion was assessed. Total renal cortex expression of Per1 and Bmal1 was assessed by immunoblotting (N=4-6/group ± SD). Results: 16M rats exhibit significantly increased MAP and 24-h sodium retention vs. 3M rats [MAP (mmHg) 3M 102±4 vs. 16M 127±5, P<0.05; 24h Na retention (mEq/24h) 3M 0.3±0.1 vs. 16M 0.8±0.2, P<0.05). 16M rats exhibit an attenuation of the circadian MAP pattern compared to 3M rats. Aged rats have a significant decrease in the blood pressure rise during the dark (active) vs. 3M rats (Dark phase increase in MAP (mmHg) 3M +13.6±2.1 vs. 16M +4.8±1.9, P<0.05). 3M rats exhibit a classical diurnal pattern of 24-h sodium excretion with increased natriuresis during the dark (active) phase – a response that is attenuated in 16M rats that exhibit a significant reduction in the increase in natriuresis in the dark phase (Light phase UNaV (μEq/12h) 3M 380±48 vs. 16M 410±36, Dark phase natriuresis 3M 620±31 vs 16M 502±27, P<0.05). 16M rats had an impaired natriuretic response to an acute oral NaCl load in the first 12h post-gavage (UNaV 12h (μEq/12h) 3M 681±42 vs. 16M 243±39, P<0.05). In 16M old rats there was no change in renal Per1 and decreased renal Bmal1 protein (Bmal1 fold change 16M vs. 3M, 0.65±0.7, P<0.05). Conclusions: We observed impaired circadian control of blood pressure and renal sodium excretion in aged male SD rats. These changes in renal sodium handling may reflect endogenous decreases in renal Bmal1 levels with age and contribute to the observed hypertensive phenotype in aged rats.

Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males

The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. Methods30 young, healthy, sodium loaded, non-obese males were exposed to −15 mmHg LBNP, −30 mmHg LBNP, −15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. ResultsAll intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; −15 mmHg: −3.1 ± 0.9 %, −30 mmHg: −2.9 ± 0.6 %, −15 mmHg + aslikiren: −1.8 ± 0.6 %). −15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. ConclusionSympathetic stimulation for 90 min via LBNP at −30 mmHg LBNP compared to −15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.

Renal sodium handling and blood pressure changes in gestational protein-restricted offspring: Role of renal nerves and ganglia neurokinin expression.

BackgroundConsidering long-term changes in renal sodium handling and blood pressure in maternal protein-restricted (LP) offspring, we assumed that the development of LP hypertension results from abnormal dorsal root ganglia (DRG) neurokinin expression associated with impaired responsiveness of renal sensory receptors, promoting a reduced urinary excretion of sodium. The present study investigates whether increased blood pressure in protein-restricted offspring would be associated with changes in the DRG cells and in renal pelvic wall expression of NK1R, SP and CGRP when compared to NP offspring. In addition, we assessed the tubular sodium handling, estimated by creatinine and lithium clearances before and after bilateral renal denervation in conscious LP offspring relative to age-matched NP counterparts.MethodsDams received a normal (NP) or low-protein diet (LP) during their entire pregnancy period. Male NP or LP offspring underwent bilateral surgical renal denervation before the 8-week renal functional test and blood pressure measurements. Immunofluorescence staining in DRG cells was assessed in optical sections by confocal laser scanning microscope.ResultsThe current data demonstrated a sustained rise in blood pressure associated with a decrease in fractional excretion of sodium (FENa) by reducing post-proximal tubule sodium rejection in 16-wk old LP rats relative to age-matched NP counterparts. According to this study, bilateral renal denervation attenuated blood pressure and increased FENa in LP offspring. Furthermore, an immunohistochemical analysis showed a reduced expression of SP and CGRP in DRGs of LP when compared with NP rats. Renal pelvis of LP rats did not show a strong CGRP expression related to NP rats, whereas there was no change in SP immunostaining.ConclusionsThese observations raise the possibility that impaired DRG and pelvic neurokinin expression associated with responsiveness of renal sensory receptors in 16-wk old LP offspring are conducive to excess renal reabsorption of sodium and development of hypertension in this programmed model.

Renal Cytochrome P450 as a Determinant of Impaired Natriuresis by PPAR‐γ Ligands in Ovariectomized Obese Rats

Peroxisome proliferator-activated receptor (PPAR)-gamma ligand, pioglitazone (PIO), is reported to induce edema especially in postmenopausal women. The aim of this study was to elucidate the mechanism for PIO-induced sodium retention and to discover the therapeutic strategy for the PIO-induced changes in renal sodium handling. Zucker obese rats were ovariectomized and were given PIO for 8 weeks. Renal sodium excretion and renal expressions of several enzymes that generate natriuretic substances were examined. Sodium excretion was decreased in ovariectomized (OVX) rats that were given PIO when compared with OVX rats that were not. Urinary nitrites/nitrates excretion was decreased in OVX rats, but was restored by PIO. The expressions of nitric oxide synthases (NOSs) and cyclooxygenases-1/2 (COX-1/2) were unaltered. Similarly, the expression of epithelial sodium channels (ENaC), identified as a PPAR-gamma-regulated gene product, was unaffected. In contrast, the expression of cytochrome P450 4A (CYP4A) was increased in OVX rats, and was downregulated by PIO. Co-treatment of OVX rats with PIO and PPAR-alpha ligand, fenofibrate, a putative inducer of CYP4A, restored not only the impaired sodium excretion but also the downregulated CYP4A expression. PIO-induced sodium retention is specific in female OVX rats. Ovariectomy decreases renal NO production, but upregulates renal CYP4A expression to compensate for renal sodium balance. In this setting, PIO downregulates CYP4A, leading to sodium retention. Furthermore, PPAR-alpha ligands can provide a novel strategy for preventing the PIO-induced sodium retention.

Effect of age on renal functional and orthostatic vascular response in healthy men.

1. Few studies have been reported concerning the effect of ageing on renal functional and vascular responses to various stresses during ordinary life. In the present study, we examined the effect of age on changes in renal sodium handling and renal vascular resistance (RVR) in response to standing from a supine position in subjects with normal renal function. 2. We selected 43 healthy males in the second through to the seventh decade of life and gave them a constant dietary sodium intake before the study period. Renal function was estimated by standard clearance methods with the subject in a state of euvolaemia. 3. The mean daily urinary excretion of sodium was 236 +/- 22 mEq. Standing from a supine position was associated with significant decreases (P < 0.0001) in creatinine clearance (from 125 +/- 18 to 117 +/- 19 mL/min per 1.73 m2), sodium excretion (from 178 +/- 29 to 97 +/- 23 microEq/min) and fractional excretion of sodium (from 1.02 +/- 0.19 to 0.60 +/- 0.13%). A significant increase (P < 0.0001) in the RVR index (from 0.11 +/- 0.03 to 0.14 +/- 0.04 units) was noted. Univariate analysis indicated that while the change in RVR associated with standing was significantly diminished (P < 0.05) in older subjects, orthostatic changes in other parameters associated with standing were minimally influenced by age. 4. In conclusion, although the renal vascular response is impaired in advanced age, the renal functional response to orthostasis is otherwise maintained in healthy elderly subjects under conditions of normal sodium intake and clinical euvolaemia.

Effect of hyperinsulinaemia on renal function and nitrate/nitrite excretion in healthy subjects.

1. In addition to its metabolic actions, insulin acts as a vasodilator in certain vascular beds, such as skeletal muscle. It has been shown that this effect is mediated by endothelium-derived nitric oxide (NO). Unlike in the skeletal muscle, insulin-NO interactions in the kidney, another major site of insulin action, have been less studied. The aim of the present study was to explore the role of NO in renal effects of hyperinsulinaemia in healthy subjects. 2. Changes in renal function and urinary nitrate/nitrite (NO2-/NO3-; Griess method) levels as a marker of renal production of NO were assessed during euglycaemic hyperinsulinaemic clamp and compared with normoinsulinaemic isovolaemic conditions (administration of the same amount of insulin/glucose-free vehicle) in 10 healthy male volunteers. 3. Hyperinsulinaemia was associated with a decrease in renal excretion of stable metabolites of NO (mean (+/- SEM) 0.56 +/- 0.12 vs 0.38 +/- 0.05 mumol/min, respectively; P < 0.05). In contrast, administration of the same volume of insulin-free vehicle resulted in elevation of urinary NO2-/NO3- (P < 0.05). The changes in renal sodium handling followed a similar pattern as changes in the renal excretion of NO2-/NO3- with a significantly different response to hyperinsulinaemia when compared with normoinsulinaemia (F = 12.2; P < 0.001). The mean arterial pressure, blood levels of low-density lipoprotein-cholesterol and free fatty acids, possible factors influencing renal and systemic NO production, remained constant throughout both experiments. 4. These results suggest that hyperinsulinaemia is associated, in healthy males, with a decrease in renal generation of NO. In contrast, mild volume expansion with insulin-free vehicle resulted in increased excretion of NO metabolites. This insulin-induced attenuation of renal NO synthesis may contribute to the anti-natriuretic actions of insulin.

Renal sodium handling in experimental diabetes: role of NO.

Recent studies have suggested that diabetes is a state of increased renal nitric oxide (NO) activity as assessed by urinary excretion of nitrites and nitrates (NOx), and that NO synthase inhibitors reverse the increased glomerular filtration rate (GFR) observed in experimental diabetes. In addition to being a potent vasodilator in the renal vasculature, NO also plays a role in modulation of renal sodium excretion. To explore the role of NO in diabetes-associated alterations in renal excretory function, renal haemodynamic and sodium handling parameters were evaluated in conscious control (C) and streptozotocin diabetic rats (D) and correlated to the renal activity of NO, as assessed by urinary excretion of its metabolites NOx. To further explore this issue, the changes in renal haemodynamics and sodium handling were also assessed after NO synthase inhibition with a non-pressor dose of L-nitro-arginine-methyl-ester (L-NAME) and after administration of the NO donor, glyceryl trinitrate (GTN). Systolic blood pressure was not different between C and D rats. D rats exhibited marked hyperglycaemia (P < 0.001), and increases in GFR (P < 0.001), renal plasma flow, filtration fraction, urinary sodium excretion (UNaV, P < 0.001), filtered load of sodium (FLNa, P < 0.01), and a decrease in fractional reabsorption of sodium (FRNa, P < 0.0001). In contrast, total reabsorption of sodium (TRNa) was increased in D rats compared to C rats (P < 0.001). The urinary excretion of NOx was markedly increased in D rats (P < 0.01). Regression analyses performed in D rats revealed a close relationship between UNaV and GFR and a weaker correlation with urinary NOx. Although FRNa correlated only with urinary excretion of NOx, there was a strong relationship between TRNa and GFR. In contrast to D rats, control rats demonstrated only a relationship between TRNa and GFR and no other correlations were found. In D rats, NO inhibition with L-NAME (1 mg/kg body weight) resulted in a marked decrease in GFR and urinary NOx associated with decreases in FLNa and TRNa but did not influence FRNa. In contrast, in C rats the post-L-NAME decrease in NOx was not associated with significant changes in GFR and renal sodium handling. GTN-treated C rats exhibited a renal vasodilatory response and an increase in natriuresis and urinary NOx whereas no renal changes were observed in D rats during GTN administration. The present data indicate that changes in renal sodium handling before and after NO modulation in experimental diabetes are related to changes in GFR rather than to the renal activity of NO. Therefore, in contrast to the effects on renal haemodynamics, NO does not play an important role in the altered renal sodium handling observed in experimental diabetes.

Renal sodium handling in experimental diabetes: role of NO

Recent studies have suggested that diabetes is a state of increased renal nitric oxide (NO) activity as assessed by urinary excretion of nitrites and nitrates (NO x ), and that NO synthase inhibitors reverse the increased glomerular filtration rate (GFR) observed in experimental diabetes. In addition to being a potent vasodilator in the renal vasculature, NO also plays a role in modulation of renal sodium excretion. To explore the role of NO in diabetes-associated alterations in renal excretory function, renal haemodynamic and sodium handling parameters were evaluated in conscious control (C) and streptozotocin diabetic rats (D) and correlated to the renal activity of NO, as assessed by urinary excretion of its metabolites NO x . To further explore this issue, the changes in renal haemodynamics and sodium handling were also assessed after NO synthase inhibition with a non-pressor dose of L-nitro-arginine-methyl-ester (L-NAME) and after administration of the NO donor, glyceryl trinitrate (GTN). Systolic blood pressure was not different between C and D rats. D rats exhibited marked hyperglycaemia ( P <0.001), and increases in GFR ( P <0.001), renal plasma flow, filtration fraction, urinary sodium excretion (U Na V, P <0.001), filtered load of sodium (FL Na , P <0.01), and a decrease in fractional reabsorption of sodium (FR Na , P <0.0001). In contrast, total reabsorption of sodium (TR Na ) was increased in D rats compared to C rats ( P <0.0001). The urinary excretion of NO was markedly increased in D rats ( P <0.01). Regression analyses performed in D rats revealed a close relationship between U Na V and GFR and a weaker correlation with urinary NO x . Although FR Na correlated only with urinary excretion of NO x , there was a strong relationship between TR Na and GFR. In contrast to D rats, control rats demonstrated only a relationship between TR Na and GFR and no other correlations were found, in D rats, NO inhibition with L-NAME (1 mg/kg body weight) resulted in a marked decrease in GFR and urinary NO x associated with decreases in FL Na and TR Na but did not influence FR Na . In contrast, in C rats the post-L-NAME decrease in NO x was not associated with significant changes in GFR and renal sodium handling. GTN-treated C rats exhibited a renal vasodilatory response and an increase in natriuresis and urinary NO x whereas no renal changes were observed in D rats during GTN administration. The present data indicate that changes in renal sodium handling before and after NO modulation in experimental diabetes are related to changes in GFR rather than to the renal activity of NO. Therefore, in contrast to the effects on renal haemodynamics, NO does not play an important role in the altered renal sodium handling observed in experimental diabetes.

Reduced liver function is the trigger for renal sodium retention following portal vein ligation in the rat.

Sodium retention along with peripheral vasodilation are features of prehepatic portal hypertension. In several models of experimental liver damage, sodium retention occurs only when hepatic function, measured by the aminopyrine breath test (ABT-k), falls below a critical threshold. The relationship between renal sodium handling, ABT-k and systemic and renal haemodynamics in partial portal vein ligated (PVL) rats was examined to test hypothesis that peripheral vasodilation was responsible for initiating sodium retention. Haemodynamic measurements were conducted early after surgery in portal hypertensive rats with and without sodium retention and in sham-operated controls. Compared with control, both PVL groups of rats had elevated portal pressure and lower peripheral vascular resistance (P < 0.05). Sodium retaining-PVL rats had both lower ABT-k (0.95 +/- 0.05 vs 1.38 +/- 0.06 x 10(-2)/min; P < 0.05) and higher sodium balance (1.38 +/- 0.09 vs 0.43 +/- 0.09 mmol/day; P < 0.05) than non-sodium retaining PVL rats. No differences in plasma renin activity or noradrenaline concentrations were observed. In a separate group of rats, hydralazine-induced pheripheral vasodilation did not induce sodium retention. These results suggest that the presence of peripheral vasodilation alone is not sufficient to trigger a sodium-retaining status. A factor, probably liver function-dependent, acting directly on renal tubules may be necessary for changes in renal sodium handling in this model.

Exaggerated natriuresis and lithium clearance in spontaneously hypertensive rats.

Since hypertension is associated with changes in the handling of various cations (including sodium and lithium) across the cell membrane, the present study investigated the validity of the lithium clearance method in hypertension by comparing two measures of proximal reabsorption. Thus, fractional lithium excretion and transit time (TT)-occlusion time (OT; e-TT/T) were determined successively in the same spontaneously hypertensive rat (SHR, Okamoto strain). The rats were examined both before and after an acute saline load. The results show that the lithium clearance method can be used for the determination of proximal reabsorption in SHR. Utilizing the lithium clearance method, the changes in renal sodium handling underlying the exaggerated natriuresis were investigated in unanaesthetized catheterized rats. It was found that the exaggerated natriuresis was associated with an increased output from the proximal tubule, whereas no difference in distal sodium handling could be detected between SHR and normotensive Wistar-Kyoto rats (WKY).

Pathogenesis of renal sodium handling in cirrhosis. A reappraisal.

In summary, it is apparent that renal sodium retention in patients with advanced liver disease constitutes a fascinating constellation with numerous and diverse causes and an elusive pathophysiology. The dissociation between hyperaldosteronism and the attendant changes in renal sodium handling and the demonstration of an impairment in natriuretic hormone release despite the absence of overt signs of sodium retention underscore the complete nature of the derangement. It is likely that the development of sodium retention necessitates the participation of several hormonal and/or neural effectors, acting in concert. Additional insight into this fascinating problem must await further biochemical characterization of some of the mediators and a delineation of their pathophysiological role.

Increased renal prostaglandins in normal pregnancy and in pregnancy with hypertension.

The 24-hour urinary excretion of prostaglandins (PGs) E2 and F2 alpha (which reflects the renal synthesis of these substances) was measured by radioimmunoassay in normal nonpregnant women (NW, n = 23), nonpregnant women suffering from essential hypertension (HW, n = 23), normal pregnant women (NP, n = 24) and women with hypertension in pregnancy (HP, n = 14). All pregnant women were in the third trimester of their pregnancy (week 24-40). The excretion of both PGE2 and PGF2 alpha was increased in NP as compared to NW. PGF2 alpha was relatively more elevated, leading to a decreased PGE2/PGF2 alpha ratio. In HP, PGE2 and PGF2 alpha excretions were even greater, and the PGE2/PGF2 alpha ratio was even lower than in NP. This contrasted with the lowered PGE2 excretion in HW. The increased renal PGs synthesis in normal pregnancy could be related to the effects on the kidney of several hormonal changes peculiar to pregnancy. In addition, the lowered PGE2/PGF2 alpha ratio suggests the possibility of an increased activity of the PGE2-9-ketoreductase, which could be related to the changes in renal sodium handling observed in pregnancy. The pattern of PGE2 excretion in HP is opposite to that observed in HW (i.e. increase rather than decrease). However, both groups share the lowered PGE2/PGF2 alpha ratio with respect to the normotensive counterparts. The causes of altered PG synthesis in pregnant women with hypertension are presently unclear.

Changes in renal sodium handling and blood pressure by the dietary sodium restriction in patients with essential hypertension

Changes in renal sodium handling and blood pressure by the dietary sodium restriction in patients with essential hypertension

Urinary calcium excretion at extremes of sodium intake in normal man.

To elucidate the relationship between the renal regulation of sodium and calcium excretion at extremes of sodium intake, we studied 6 normal men ingesting a fixed, 400 mg/day calcium intake and four levels of sodium intake from 10 to 1,500 mEq/day. Serum ionized calcium was not influenced by sodium intake. Blood pressure and cardiac index increased modestly. Urinary calcium excretion increased to 262 +/- 53 mg/day (mean +/- SE). Plasma norepinephrine concentration, serum PTH levels, hematocrit, total serum protein concentrations and CO2 content decreased with increasing sodium intake. Urinary cAMP increased as sodium intake was raised from 10 to 300 mEq/day, but subsequently decreased to basal values. Urinary calcium and sodium excretion were related (p less than 0.001) in a nonlinear fashion as were the fractional excretions of these cations (p less than 0.001). The filtered calcium load and the fractional calcium excretion were directly and linearly related (p less than 0.001). We conclude that the effect of sodium intake on urinary calcium excretion principally reflects changes in the filtered calcium load rather than changes in renal sodium handling. Calcium homeostasis at extremes of sodium intake does not appear to be critically dependent upon PTH-mediated mechanisms. The data suggest that the proximal tubule has a remarkable capacity to dissociate calcium resorption from that of sodium.

EARLY RENAL FUNCTION ALTERATIONS IN CHILDREN WITH ACUTE GLOMERULONEPHRITIS (AGN)

Inability to increase fractional excretion of filtered sodium (FENa) after sodium loading has been demonstrated in experimental AGN. Adult patients with AGN show FENa below 1.0. Since early changes in renal sodium handling in children with AGN are lacking, we studied 41 patients with post-streptococcal AGN (3 to 12 yrs. old). They all had hypertension with no previous treatment. The following urine-to-plasma ratio (UP) indices were studied: urea, osmolality, sodium, creatinine (Cr), and FENa. Patients were distributed into 3 groups: (I): 1-5 days of evolution, 18 cases; (II): 6 to 10 days, 15 cases; (III): 11 to 15 days, 8 cases. FENa in I was below 1.0 (x = 0.29 ± 0.39); most cases of II and III were above 1.0(x = 1.0 ± 0.7 and 1.6 ± 1.1 respectively; p < 0.01 between I and II and I and III). UPCr and UCr were: I) 245 ± 170 and 236 ± 144; 11) 61 ± 37 and 67 ± 50; III) 69 ± 70 and 62 ± 54 (p < 0.01 between I and 11 and I and III). No difference of age, sex and the other indices between the 3 groups were found. Our results show progresive increase of FENa in relation with time of evolution, depending on UCr changes. Early higher values of UCr suggest a temporary compensatory increase of glomerular filtration rate, probably secondary to hypervolemia. Hypervolemia might be produced by initial hemodynamic changes resulting from glomerular injury.