Renal Sodium Excretion Research Articles

Abstract 064: 20-HETE Contributes to Vasoconstriction of Renal Microvessels and Sodium Retention in Cyp4a14-/- Mice, a Model of 20-HETE Dependent Hypertension

20-HETE (20-Hydroxyeicosatetraenoic acid), is a cytochrome P450 (CYP) 4A-derived arachidonic acid metabolite. 20-HETE has been linked to both pro-hypertensive (via increased vasoconstriction, vascular remodeling and vascular injury of renal microvessels) and anti-hypertensive (inhibiting ion transport in the distal nephron) functions. In this study we examined the effect of 20-SOLA (2,5,8,11,14,17-hexaoxanonadecan-19-yl-20-hydroxyeicosa-6(Z),15(Z)-dienoate), a water soluble antagonist of the actions of 20-HETE on renal hemodynamics and sodium (Na) excretion in Cyp4a14 knockout (CYP4a14-/-) male mice. The CYP4a14-/- male mice display hypertension accompanied by increased vascular 20-HETE levels. Administration of 20-SOLA (10mg/kg/day in drinking water) normalized blood pressure (BP) in male Cyp4a14-/- mice at day 10 of treatment (124±1 vs. 153±2 mmHg in untreated male Cyp4a14-/- mice; p<0.05). The normalization of blood pressure was accompanied by transient increase in the urinary sodium excretion in the Cyp4a14-/- male mice (8.3±0.7 vs. 5.8±0.5 μmol/g body weight/day; p<0.05). Importantly, 20-SOLA increased glomerular filtration rate (GFR) of Cyp4a14-/- mice (2.38±0.05 vs. 1.88±0.18 μL/min/mg kidney weight, p<0.05) as opposed to no changes observed in the wild type (WT: (2.26±0.18 vs. 2.33±0.20μL/min/mg kidney weight). Evaluation of the renal blood flow (RBF) by laser Doppler flowmetry showed that treatment with 20-SOLA increased the RBF in Cyp4a14-/- mice by 12.3±4%, which remained unaltered in the WT. Additionally, the pressure-induced myogenic tone of isolated preglomerular microvessels was significantly elevated in Cyp4a14-/- mice; 20-SOLA treatment prevented the increase in myogenic responses. The natriuretic response to an isotonic saline loading challenge (10% of body weight, IP) was significantly attenuated in the Cyp4a14-/- mice as compared to the WT (35.5±2.8 vs. 57.4±8.3 percentage of Na load, p<0.05); this was corrected by 20-SOLA (61.7±5.7 percentage of Na load, p<0.05). These results confirm that 20-SOLA normalizes blood pressure of Cyp4a14-/- male mice and demonstrates that this is associated with increases in GFR, RBF and natriuresis.

Abstract P628: Angiotensin 1-7 Mas Receptor and Dopamine D1 receptor Interaction as a Novel Natriuretic Mechanism in Rat Kidneys

Evidence to date suggests that a positive interaction between natriuretic factors promotes sodium excretion to maintain sodium homeostasis and blood pressure. Although the involvement of renal dopamine D1 receptor (D1R) in promoting sodium excretion is well established; the role of Angiotensin (Ang) 1-7 Mas receptor (MasR) is not clear. Here we provide evidence for a functional interaction between these two renal G protein-coupled receptors which suggests that natriuretic response to Ang 1-7 via MasR is dependent on D1R activation. Male Sprague Dawley rats of comparable weight and age were infused with Ang 1-7, MasR antagonist DPro, D1R agonist SKF38393 and D1R antagonist SCH23390. Blood pressure was monitored throughout the experimental procedure and none of the infused drugs affected the pressure. Animals infused with saline alone served as controls. Infusion of Ang1-7 caused significant natriuresis and robust diuresis compared to saline. SKF38393 infusion also induced significant natriuresis and diuresis when compared to saline infusion. Both natriuretic and diuretic response to Ang 1-7 was blocked by Dpro and SCH23390. However, Dpro failed to block SKF38393 response. Concomitant infusion of SKF38393 and Ang 1-7 did not show a cumulative natriuretic or diuretic effect when compared to SKF38393 or Ang 1-7 infusion alone. FENa (%), control (saline): 0.30 ± 0.09; Ang 1-7: 1.03 ± 0.21; Ang 1-7 plus Dpro: 0.49 ± 0.11; Ang 1-7 plus SCH23390: 0.36 ± 0.10; SKF38393: 0.83 ± 0.16; SKF38393 plus SCH23390: 0.41 ± 0.09; SKF38393 plus Dpro: 0.82 ± 0.17; Ang 1-7 plus SKF38393: 1.06 ± 0.21. These data suggest that Ang 1-7 via MasR causes natriuresis which is dependent on D1R activation. On the other hand, renal D1R-mediated sodium excretion is independent of MasR. This study is a paradigm shift as these data identify a novel functional unidirectional interaction between renal MasR and D1R which deviates from commonly known receptor-receptor interaction.

Abstract P166: The Effects of V2 Receptor Antagonist Treatment on the Renal Medullary Circulation and Urinary Sodium Excretion in Rat

Objective: V2 receptor (V2R) antagonist increases aquaresis, and was reported to have renoprotective and natriuretic effect, although the mechanism is not fully clarified. Renal medullary hemodynamics contributes sodium retention and renal injury. Therefore, the present study was designed to evaluate the effect of V2R antagonist on renal medullary blood flow. Methods: Catheter was inserted in femoral artery and vein of anesthetized SD rats to monitor blood pressure (BP), heart rate (HR) and to infuse drugs, respectively. Renal medullary blood flow (MBF) and renal medullary oxygen pressure (pO2) were measured with laser-Doppler flowmetry or oxygen microelectrode, respectively. V2R antagonist, OPC-31260 (OPC, 0.25mg/kg bw/h) or furosemide (Furo, 0.5mg/kg bw/h) was intravenously administrated for 90min. Urine was collected in 30 min interval and urinary sodium (UNaV), hydrogen peroxide (UH2O2V) and [nitrate + nitrite] (UNOxV) excretion were measured. Results: OPC and Furo treatment did not change BP and HR. Urine volume was significantly increased by OPC (1.1+0.2 to 6.1+0.5 g/30 min) and Furo (1.4+0.6 to 4.7+0.3 g/30 min) treatment but was not different between groups. MBF was significantly decreased in Furo (12+4% decrease from baseline), while OPC did not changed MBF (1+3% increase from baseline). pO2 was significantly increased by both OPC and Furo treatment (20+6 and 27+10% increase from baseline, respectively). UNaV was significantly increased in OPC (0.10+0.02 to 0.44+0.05 mEq/30 min) and Furo (0.14+0.08 to 0.69+0.06 mEq/30 min) treatment, the increase of UNaV was significantly higher in Furo than OPC group. UH2O2V was significantly increased by Furo treatment (16+4 to 28+6 nmol/30 min), while did not change in OPC treatment (10+2 to 19+4 nmol/30 min). UNOx was significantly increased in OPC treatment (211+30 to 376+45 nmol/30 min), while did not change in Furo treatment (142+27 to 237+75 nmol/30 min). Conclusion: OPC treatment increased NO production. Increased NO could contribute to decrease of sodium reabsorption, result in increase of renal medullary pO2. This scheme could be one on the mechanisms of renal protective effect by V2R antagonist treatment.

Abstract 106: Hypothalamic PVN GαI2 Protein-mediated Renal Nerve Dependent Sympathoinhibition Facilitates Suppression of NCC Activity and a Salt-resistant Phenotype

Aim: We hypothesize hypothalamic paraventricular (PVN) specific Gαi2 proteins, which are up-regulated in the PVN during increased sodium intake, mediate global and renal sympathoinhibition to facilitate suppression of the activity of the sodium chloride cotransporter (NCC) and salt-resistance in the Sprague Dawley rat. Methods: Groups of intact or bilateral renal denervated (RDNX) salt-resistant Sprague-Dawley rats received a bilateral PVN infusion of a scrambled (SCR) or Gαi2 oligodeoxynucleotide (ODN-300ng/side/day) and a normal 0.4% (NS) or high 8% NaCl (HS) diet for 7-days. On day-7 24h Na+ balance was assessed - in sub-groups MAP, plasma norepinephrine (NE) content, kidney NE content and NCC activity (peak natriuresis to iv bolus hydrochlorothiazide (HCTZ)) was assessed (N=6/gp/study). Results: In SCR ODN infused rats HS-intake evoked a significant 3-fold site-specific increase in PVN Gαi2 proteins and suppressed plasma NE content (plasma NE [nmol/L] SCR NS 72±4 vs HS 40±5, P<0.05), endogenous kidney NE content (NE [pg/m] SCR NS 586±36 vs HS 496±41, P<0.05) and NCC activity (peak ΔUNaV to HCTZ [μeq/min] SCR NS 10.6±0.8 vs HS 7±1, P<0.05) without impacting sodium homeostasis or MAP. ODN-mediated PVN Gαi2 down-regulation caused renal nerve-dependent hypertension (MAP [mmHg] Gαi2 NS 126±2, Gαi2 HS 147±2, Gαi2 HS + RDNX 131±3 P<0.05) sodium retention (24h Na+ balance [meq] Gαi2 NS 0.6±0.3, Gαi2 HS 2.3±0.4, Gαi2 HS + RDNX 0.8±0.3 P<0.05), global and renal sympathoexcitation (plasma NE [nmol/L] Gαi2 NS 67±7, Gαi2 HS 105±11, Gαi2 HS + RDNX 74±6 P<0.05; kidney NE content [pg/mg] Gαi2 NS 614±48 vs HS 823±59, P<0.05) and a failure to suppress NCC activity (peak ΔUNaV to HCTZ [μeq/min] Gαi2 NS 10.2±2, Gαi2 HS 14.7±2, Gαi2 HS + RDNX 7.6±2, P<0.05). Conclusion: PVN Gαi2 protein-gated pathways represent a sodium sensitive CNS mechanism acting to regulate renal nerve-dependent sodium excretion via, in part, actions upon the activity of the NCC. Based on recent studies by other groups we speculate the regulation of NCC in this setting is mediated by the actions of NE released from efferent renal nerves on renal adrenoceptors to impact the signal transduction network that regulates NCC expression.

Abstract 137: Conditional Knockout of Sphingosine-1-Phosphate Receptor 1 in Renal Collecting Ducts Promotes Sodium Retention in Mice

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite formed by phosphorylation of sphingosine. We have recently shown that renal medullary infusion of S1P agonist increases sodium excretion possibly through inhibition of epithelial sodium channel (ENaC) activity via S1P receptor 1 (S1P1), which is prominently localized in the collecting ducts. The present study was to test the hypothesis that the S1P1 in collecting duct plays a pivotal role in the regulation of renal sodium handling. We generated conditional knocked-out (CKO) mice with collecting duct-specific ablation of S1P1 using loxP-Cre system. Functionally, urinary sodium excretion in S1P1 CKO mice was significantly decreased by about 60% compared with that in control mice after acute IV sodium loading (0.84±0.16 vs. 2.22±0.62 μmole/min/g kwt). Moreover, the pressure natriuresis was severely impaired in S1P1 CKO mice compared with that in the control mice (4.32±1.04 vs. 8.73±0.19 μmole/min/g kwt). Furthermore, chronic high salt-induced sodium retention was remarkably enhanced in S1P1 CKO mice comparing to the control animals (5.27±0.39 vs. 2.38±1.04 mmole/24h/100g bw). Our results suggested that S1P1 in collecting duct plays an important role in the regulation of renal sodium excretion and that deficiency of S1P1 in collecting duct impairs renal sodium handling and promotes sodium retention. Modulation of S1P1 function in the renal medulla could be a therapeutic approach for salt-sensitive hypertension.

Abstract 087: Human Stomach Cell Gastrin Inhibits Renal NHE3 and NaKATPase in Concert With the Renal D1R

The digestive track secretes gastrin in response to sodium ingestion stimulating increased renal sodium excretion. We previously showed that gastrin secreted by human colon cancer cells (SW626) can bind to cell surface cholecystokinin receptors on renal proximal tubule cells (RPTC), modulating the natriuretic dopaminergic system. We tested the hypothesis that a similar gastro/renal axis exists in humans. Novel human stomach antrum G-cell lines from 6 separate individuals were isolated and each shown to express gastrin mRNA and protein, and bind Phaseolus vulgaris Leucoagglutinin (PHA-l) by fluorescence lectin affinity (marker for gastrin secreting cells). It was determined that the D1 receptor (D1R) is also found on G-Cells. In human stomach tissue, gastrin expression was increased by Fenofibrate treatment, (PPARα agonist, p= 0.07, in 3 live ex-vivo cultured human stomachs). Moreover, we tested the effect of gastrin on CCKB2 receptors in human RPTC. Gastrin (100 nM 15 min.) increased RPTC phospholipace-C (PLC) activity by 1.07± 0.01 fold, N=35, p<0.0001, using a PLC-FRET biosensor, CYPHR, but did not increase cAMP levels using the specific cAMP-FRET biosensor, ICUE-YR. Both gastrin and SKF83822 (100 nM, a cAMP specific D1R agonist, 15 min) alone reduced sodium influx into RPTC via NHE3 (from VEH 100± 4.7% to 73.5± 6.2% or 74.1± 4.3% respectively N=6, p<0.05), but gastrin along with SKF83822 decreased sodium influx more than either alone (57.2 ± 5.8% N=6, p<0.05). Sodium efflux via NaKATPase was reduced by SKF83822 (from VEH 100± 3.9% to 84.2± 3.3%, N=6, p<0.05), but not gastrin alone, however SKF83822 along with gastrin reduced sodium efflux more than SKF83822 alone (72.3±5.1% vs N=6, p<0.05). Additionally we found that Angiotensin II (AngII, 10 nM, 15 min.) increased NHE3 activity (12.3± 3.6% N=6, p<0.01) and this increase was completely blocked by gastrin (N=6, p<0.01). The PLC inhibitor U73122 reversed the inhibitory effect of gastrin on NHE3 and NaKATPase. Gastrin was also found to decrease the amount of fluorescent AngII binding to RPTCs (27.4± 6.1% N=6, p<0.01) and this decrease was completely blocked by U73122. Thus, both stomach gastrin and the renal D1R inhibit NHE3 and NaKATPase, to increase sodium elimination from the body after salt is ingested.

Editorial: Natriuretic Hormones.

Editorial: Natriuretic Hormones.

Iatrogenic electrolyte disorders

The maintenance of water and electrolyte homeostasis is of enormous importance for the functioning of cells and tissues. A number of therapeutic procedures intentionally or unintentionally influence important regulatory mechanisms of these interdependent balanced systems. Excessive salt intake doesn't only expand the extracellular volume; it can also cause a considerable increase in tonicity. Owing to its insulin-dependent duality of action, glucose can represent an effective or an ineffective osmolyte. This fact has to be considered in patients with diabetic ketoacidosis. Diuretics reduce the volume expansion via renal excretion of sodium (and water); however, in addition to hypokalemia, diuretics can also cause severe alkalosis. Nowadays, hemodialysis is a routine procedure-but even routine procedures can deliver undesirable surprises. Can dialysis cause an increase in calcium levels, or does the procedure remove therapeutically administered radioactive iodine? The current article presents a series of cases we have come across in recent years. These case reports illustrate common, but also rare iatrogenic situations. The discussion of these cases is aimed at raising awareness of the issues involved in a pathophysiological approach to clinical problems.

Effect of Treatment on Body Fluid in Patients with Unilateral Aldosterone Producing Adenoma

Background: There is limited information about the effect of prolonged aldosterone excess and treatment on body fluid. Objective: To investigate the effects of adrenalectomy versus spironolactone treatment on body composition in primary aldosteronism (PA) patients with unilateral aldosterone producing adenoma (APA). Method: We determined body composition changes assessed by a bio-impedance spectroscopy device, the Body Composition Monitor (BCM). We examined pretreatment relative overhydration (%), relative fat (%) and relative lean tissue mass (%) in PA patients with APA and followed-up with patients after adrenalectomy or spironolactone treatment. We also assessed biomarkers related to fluid overload. Results: This prospective, multicenter study included 41 PA patients with APA. Twenty-one patients received adrenalectomy, whereas 20 patients were treated with spironolactone. Patients with APA receiving adrenalectomy, as compared with those treated with spironolactone, had significantly lower relative OH (p = 0.011) and urine albumin excretion (p = 0.003), and significantly higher urine sodium excretion (p < 0.001) and relative fat (p = 0.034) four weeks after treatment. These differences dissipated 12 weeks after the initial treatment. Patients who underwent adrenaelctomy had significantly decreased TNF-α and increased serum potassium level when compared to patients treated with spironolactone 4 and 12 weeks after treatment. Conclusions: In this pilot study, we found that adrenalectomy leads to the normalization of plasma aldosterone concentration followed by an earlier increase in renal sodium excretion and decreases in body fluid content, TNF-α, and urine albumin excretion. Adrenalectomy yields a therapeutic effect more rapidly, which has been shown to ameliorate overhydration in PA patients.

Dietary Potassium a Neglected Factor in Hypertension: Morphofunctional Evidence for Regulation of Cyclooxygenase‐2 and Kallikrein by Potassium

The importance placed on dietary potassium on health and disease is underscored compared with dietary sodium, and less effort has been placed on studies on adequate dietary potassium. The benefits of potassium rich‐food are known, however, the mechanisms of action are lacking. With the hypotheses that dietary potassium regulates renal sodium excretory hormones, we studied the effect of enriched potassium diet on kallikrein (Kall) and cyclooxygenase‐2 (COX‐2)SD male rats on normal potassium diet (0.9%, NK) or higher potassium diet (3%, HK) for 4 weeks, Kidney tissue was used for protein (Western blot), mRNA (RT‐qPCR), and cell features using immunohistochemistry (IHC). Kall was restricted to connecting tubule cells CNTc, HK increased the CNTc size and immunostaining with an hypertrophied pattern, increased Golgi and secretory‐like vesicles. Kallikrein increased its enzyme activity (42±3 vs 27±3 mU, p&lt;0.005), protein by Western blot (1.3 fold p&lt;0.05), and mRNA by qRT‐PCR (1.4 fold p&lt;0.05). Kall activity correlated with UV potassium excretion (r=0.66, p&lt;0.001). COX‐2 containing cells were restricted thick ascending limb cells TAL, in response to HK was observed a decreased COX‐2 cells number, a decreased protein level (0.4 fold p&lt;0.05) and mRNA (0.5 fold p&lt;0.05).There is a different cellular response of CNTc and TAL to higher potassium diet, Kallikrein CNTc respond with hypertrophy and increased synthesis, COX‐2 TAL cells respond by decreasing the number of cells, a recruitment phenomenon. Upregulation of Kall is consistent with its vasodilatory, natriuretic effect. Downregulation of COX‐2 requires further studies to elucidate its response to potassium.

64-Year-Old Woman With Diarrhea and Increased Abdominal Girth

64-year-old woman presented to our institution for evaluation of diarrhea and increasing abdominal girth. She had a 1-month history of postprandial diarrhea unrelated to the type of foods she consumed. Her stool was watery, with no evidence of gastrointestinal bleeding. Concurrently, she also noted increasing abdominal girth requiring new pants with a larger waist size. She had no abdominal pain, nausea/vomiting, flushing, light-headedness, or constitutional symptoms. Her medical history was notable for a previous stroke with a mild residual right hand tremor. She was a lifetime nonsmoker, had no history of illicit drug use, and drank alcohol rarely. She had no history of recent travel, infectious exposures, new medications, or herbal supplement intake. Her blood pressure was 136/83 mm Hg, and herheart rate was 98beats/min.Heroxygensaturation was 95% while she breathed room air, and her respiratory rate was 18 breaths/min. Her temperature was 36.9C. Her mental status was normal. Her abdomen was soft, nontender, and mildly distended with hyperactive bowel sounds. Shifting dullness with a fluid wave was present. 1. Which one of the following is the most appropriate diagnostic approach to evaluate the patient’s abdominal symptoms? a. Paracentesis b. Colonoscopy c. Clostridium difficile toxicology screen or polymerase chain reaction d. Serology testing for transglutaminase antibody e. Abdominal radiography

The importance of intake: a gut feeling.

Limiting enteric sodium absorption is an attractive option when renal sodium excretion is disturbed. An effective approach in the gut appears to be inhibition of the electroneutral Na(+)/H(+) exchangers (NHE), in particular NHE3. Recently, fluid retention, blood pressure and target organ injury were limited in rats with cardiorenal syndrome when treated with the NHE3 inhibitor tenapanor. The downside was that the osmotic fecal load leads to watery feces. Tenapanor also induced marked reductions in enteric phosphorus absorption in rats with cardiorenal syndrome on a high phosphorus intake and resulted in marked reductions in renal injury and practically prevented vascular calcification. We have yet to discover the clinical relevance in volume terms and vascular calcifications in patients in relation to the tolerated dose. However, even if the tenapanor-induced reduction in sodium adsorption is limited in humins, combination of tenapanor therapy with diuretics may be an interesting option in selected patients.

Lack of an effect of nephron-specific deletion of adenylyl cyclase 3 on renal sodium and water excretion or arterial pressure.

Adenylyl cyclase (AC)-stimulated cAMP plays a key role in modulating transport and channel activity along the nephron. However, the role of individual adenylyl cyclase isoforms in such regulation is largely unknown. Since adenylyl cyclase 3 (AC3) is expressed throughout nephron, we investigated its role in the physiologic regulation of renal Na+ and water transport. Mice were generated with inducible nephron knockout of AC3 (AC3 KO) by breeding mice with loxP-flanked critical exons in the Adcy3 gene with mice expressing Pax8-rtTA and LC-1 transgenes. After doxycycline treatment at 1 month of age, nephron AC3 KO mice had 100% Adcy3 gene recombination in all renal tubule segments, but not in glomeruli. Sodium intake, urinary Na+ excretion, glomerular filtration rate, and blood pressure were similar between nephron KO mice and the controls during normal, high, and low Na+ diets. Plasma renin concentration was not different between the two groups during varied Na+ intake. Moreover, there were no differences in urine volume and urine osmolality between the two genotypes during normal or restricted water intake. In conclusion, these data suggested that AC3 is not involved in the physiological regulation of nephron Na+ and water handling.

Altered urinary sodium excretion response after central cholinergic and adrenergic stimulation of adult spontaneously hypertensive rats.

In this study, we hypothesized that blunting of the natriuresis response to intracerebroventricularly (i.c.v.) microinjected cholinergic and adrenergic agonists is involved in the development of hypertension in spontaneously hypertensive rats (SHR). We evaluated the effect of i.c.v. injection of cholinergic and noradrenergic agonists, at increasing concentrations, and of muscarinic cholinergic and α1 and α2-adrenoceptor antagonists on blood pressure and urinary sodium handling in SHR, compared with age-matched Wistar Kyoto rats (WR). We confirmed that CCh and NE microinjected into the lateral ventricle (LV) of conscious rats leads to enhanced natriuresis. This response was associated with increased proximal and post-proximal sodium excretion accompanied by an unchanged rate of glomerular filtration. We showed that cholinergic-induced natriuresis in WR and SHR was attenuated by previous i.c.v. administration of atropine and was significantly lower in the hypertensive strain than in WR. In both groups the natriuretic effect of injection of noradrenaline into the LV was abolished by previous local injection of an α1-adrenoceptor antagonist (prazosin). Conversely, LV α2-adrenoceptor antagonist (yohimbine) administration potentiated the action of noradrenaline. The LV yohimbine pretreatment normalized urinary sodium excretion in SHR compared with age-matched WR. In conclusion, these are, as far as we are aware, the first results showing the importance of interaction of central cholinergic and/or noradrenergic receptors in the pathogenesis of spontaneous hypertension. These experiments also provide good evidence of the existence of a central adrenergic mechanism consisting of α1 and α2-adrenoceptors which works antagonistically on regulation of renal sodium excretion.

Does dopamine connect the dots in ADPKD?

Healthy autosomal dominant polycystic kidney disease (ADPKD) patients with normal kidney function demonstrate reduced endothelial-dependent vasodilation that improves with increasing local dopamine levels. Dopamine regulates renal sodium excretion, and dopamine receptors are located on primary cilia in both vascular and renal tubular epithelial cells. The study by Lorthioir and colleagues links endothelial function and dopamine availability in ADPKD patients.

Decrease of Urotensin II activity can impact on the volume status in predialysis chronic kidney disease

Urotensin II (U-II) was thought to be one of the mediators of primary renal sodium retention due to effects on renal sodium excretion. For this purpose, the relationship between U-II and overhydration was investigated. A total of 107 patients were enrolled in the study. According to body compositor monitor analysis, fluid overload up to 1.1 L, was considered normohydration. Patients were divided according to hydration status; overhydrate (n = 42) and normohydrate (n = 65) were studied in both groups. Pulse waveform velocity propagation for arterial stiffness and blood pressure analysis and echocardiographic left ventricular and left atrial indices were performed with known fluid overload-related parameters. U-II levels were measured by using Human ELISA kit. In overhydrated group, U-II levels were significantly lower. All parameters (blood pressure, arterial stiffness parameters, echocardiographic data, age, gender, diabetes, U-II, hemoglobin) correlated with overhydration, were determined by linear regression model (method = enter), when considered together, U-II was found to be an independent predictor from other conventional overhydration-related parameters. Male sex, left ventricular mass index, left atrial volume index, hemoglobin value were found to be independent predictors for overhydration. Considering the association of low U-II levels with adverse cardiovascular events and its role in sodium retention, we think that low U-II levels can be accepted as a potential therapeutic target in patients with hypervolemic cardio-renal syndrome.

Renal dopaminergic system: Pathophysiological implications and clinical perspectives

Fluid homeostasis, blood pressure and redox balance in the kidney are regulated by an intricate interaction between local and systemic anti-natriuretic and natriuretic systems. Intrarenal dopamine plays a central role on this interactive network. By activating specific receptors, dopamine promotes sodium excretion and stimulates anti-oxidant and anti-inflammatory pathways. Different pathological scenarios where renal sodium excretion is dysregulated, as in nephrotic syndrome, hypertension and renal inflammation, can be associated with impaired action of renal dopamine including alteration in biosynthesis, dopamine receptor expression and signal transduction. Given its properties on the regulation of renal blood flow and sodium excretion, exogenous dopamine has been postulated as a potential therapeutic strategy to prevent renal failure in critically ill patients. The aim of this review is to update and discuss on the most recent findings about renal dopaminergic system and its role in several diseases involving the kidneys and the potential use of dopamine as a nephroprotective agent.

The interrelationship between cholinergic pathway in the magnocellular paraventricular nucleus and natriuresis.

The central nervous system is known to play important roles in the regulation of renal sodium excretion. The present study was designed to reveal the interrelationship between cholinergic pathway in the magnocellular paraventricular nucleus (PVN) and the natriuresis induced by brain cholinergic stimuli. The results indicated that urinary sodium excretion was significantly increased at 40 min after intracerebroventricular (ICV) injection of carbachol (CBC). Immunohistochemical studies showed that CBC increased choline acetyltransferase-immunoreactivity (ChAT-IR) in the magnocellular PVN and renal proximal convoluted tubule (PCT), respectively. After pretreatment with atropine, urinary sodium excretion was significantly reduced, and carbachol-increased ChAT-IR in the magnocellular PVN and PCT was also significantly decreased. These results suggested that brain cholinergic stimuli induced the natriuresis and increased the activity of cholinergic neurons in the magnocellular PVN and cholinergic system in the PCT. The blockade of muscarinic receptor completely abolished the natriuresis and partially inhibited carbachol-exerted stimulatory effects in the magnocellular PVN and PCT. To summarize, brain cholinergic pathway and peripheral cholinergic system in kidney were found to contribute to the natriuresis following brain cholinergic stimulation. Our findings revealed novel evidence that PVN was involved in the natriuresis via humoral mechanisms.

Renal P2 receptors and hypertension.

The regulation of extracellular fluid volume is a key component of blood pressure homeostasis. Long-term blood pressure is stabilized by the acute pressure natriuresis response by which changes in renal perfusion pressure evoke corresponding changes in renal sodium excretion. A wealth of experimental evidence suggests that a defect in the pressure natriuresis response contributes to the development and maintenance of hypertension. The mechanisms underlying the relationship between renal perfusion pressure and sodium excretion are incompletely understood. Increased blood flow through the vasa recta increases renal interstitial hydrostatic pressure, thereby reducing the driving force for transepithelial sodium reabsorption. Paracrine signalling also contributes to the overall natriuretic response by inhibiting tubular sodium reabsorption in several nephron segments. In this brief review, we discuss the role of purinergic signalling in the renal control of blood pressure. ATP is released from renal tubule and vascular cells in response to increased flow and can activate P2 receptor subtypes expressed in both epithelial and vascular endothelial/smooth muscle cells. In concert, these effects integrate the vascular and tubular responses to increased perfusion pressure and targeting P2 receptors, particularly P2X7, may prove beneficial for treatment of hypertension.

Signaling pathways involved in renal oxidative injury: role of the vasoactive peptides and the renal dopaminergic system.

The physiological hydroelectrolytic balance and the redox steady state in the kidney are accomplished by an intricate interaction between signals from extrarenal and intrarenal sources and between antinatriuretic and natriuretic factors. Angiotensin II, atrial natriuretic peptide and intrarenal dopamine play a pivotal role in this interactive network. The balance between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide, by one side, and the prooxidant effect of the renin angiotensin system, by the other side, contributes to ensuring the normal function of the kidney. Different pathological scenarios, as nephrotic syndrome and hypertension, where renal sodium excretion is altered, are associated with an impaired interaction between two natriuretic systems as the renal dopaminergic system and atrial natriuretic peptide that may be involved in the pathogenesis of renal diseases. The aim of this review is to update and comment the most recent evidences about the intracellular pathways involved in the relationship between endogenous antioxidant agents like the renal dopaminergic system and atrial natriuretic peptide and the prooxidant effect of the renin angiotensin system in the pathogenesis of renal inflammation.