Affect Sodium Transport Research Articles

Low renin forms of monogenic hypertension: review of the evidence

<b>Background:</b> Monogenic hypertension syndromes result from a single genetic mutation and present with severe, refractory hypertension, distinct laboratory abnormalities, and a positive family history. These syndromes are often unrecognized or misdiagnosed as essential hypertension, thus preventing proper treatment. The rise of molecular genetics has brought these conditions to the limelight, and physicians must be kept abreast of the latest in this field. This paper aims to educate doctors to recognize and institute appropriate management early to prevent end-organ damage.<br /> <b>Discussion: </b>These syndromes all affect sodium transport in the distal nephron of the kidneys. However, they are divided based on the location of the primary disorder, i.e., the adrenal glands or the distal nephron and discussed in that manner. Tables provide an overview of the different syndromes and provide essential information in a snapshot.<br /> <b>Conclusion:</b> The widespread availability of genetic testing facilities will aid in the earlier diagnosis of these conditions to prevent morbidity.

Role of Dipeptidyl Peptidase 4 and Effects of a Western Diet in Renal Sodium Transport and Tubular Injury

The protein dipeptidyl peptidase 4 (DPP4) is a target in the management of Type 2 diabetes mellitus (T2DM) and inhibition decreases albuminuria in humans with high cardiovascular risk such as subjects with T2DM, obesity/insulin resistance and hypertension. Our laboratory and others have shown that inhibition or genetic deletion of DPP4 has nephroprotective effects not only in rodent models of DM/insulin resistance but also obesity and hypertension. In addition, all three conditions with high cardiovascular risk are characterized by sodium retention. Recent data shows that DPP4 may affect sodium transport within the kidney via binding to sodium/hydrogen exchanger 3 (NHE3) and translocating to the villi in the brush border of the tubules. We have observed increased tubular damage and sodium uptake in a high fat/high sugar diet (Western diet) model of obesity in the setting of increased DPP4 activity. Therefore, we hypothesized that reduction/suppression of DPP4 expression/signaling and/or activity may lead to decreased sodium retention in the kidney in the obese mice.MethodsProximal tubule specific DPP4fl/fl;SGLT2Cre+ (PT DPP4KO) and DPP4fl/fl;SGLT2Cre‐ (PT DPP4WT) mice were fed a WD and control chow (CD) till sacrifice (18 to 27 mths). 24 hour urine collection and measurement of sodium excretion was done in these mice while on the diets. Gene and protein expression of transporters (sodium and water) was quantitated. Whole body DPP4‐/‐ (DPP4KO) and DPP4+/+ (DPP4WT) were on control chow diet and placed in metabolic cages for sodium balance studies. On days 3 and 4, mice were given 1% NaCl in drinking water. Daily mice weight, food and water consumption and urinary excretion of sodium and potassium and creatinine were measured.ResultsThe PT DPP4WT mice showed a much reduced 24 hour excretion of sodium compared to the PT DPP4KO mice (p<0.05) which was consistent with data from DPP4WT and DPP4KO mice on WD (unpublished) as well as data from DPP4 inhibitor treated mice (Nistala et al, Endocrinology 2014 Jun;155(6):2266‐76). Urinary sodium excretion was increased in both DPP4WT and DPP4KO mice on 1% NaCl in drinking water but the excretion was significantly increased in DPP4KO mice compared to DPP4WT mice. Excretion of glucose and other electrolytes reached a peak on the 3rd day and tapered off slightly on the 4th day. The increased excretion of sodium and water as well as slight reduction in food intake, led to gradual decrease in weight of the animals (~1gm) which was not significant between the WT and KO groups. The gene expression of many sodium and water transporters increased including NHE3, ENaCγ and AQP1/2 in the PT DPP4WT mice, while expression was reduced in the PT DPP4KO mice fed a Western Diet. The protein expression of NHE3 increased in WT mice and was suppressed in KO mice.ConclusionDPP4 expression was increased in PT DPP4WT mice fed a Western diet and reduced in the KO mice and this correlated with increased expression of NHE3 in the WT and reduction in KO mice. In the whole body DPP4KO mice, lack of DPP4 led to greater increase in sodium and water excretion. Taken together, proximal tubule DPP4 may be involved in regulating sodium and water homeostasis in CD and WD‐fed mice. Sodium excretion under conditions of low salt diet will help establish DPP4's role in sodium homeostasis.

Effects of atrial natriuretic peptide on mitochondria function in cortical collecting duct cells

BackgroundAtrial natriuretic peptide (ANP) is a hormone released from cardiomyocytes in response to cardiac wall stretching. ANP acts on the kidney by promoting sodium and water excretion as well as providing a general vasodilatory effect. Direct application of ANP has been shown to reduce sodium reabsorption in the renal tubular cells. Recently, it has been discovered that natriuretic peptides (NPs) are involved in lipolysis, lipid oxidation, and mitochondrial respiration. Evidence of a correlation between the activity of the NP system and mitochondrial respiration and biogenesis has been explored to some extent; however, little is known about these pathways in the kidney. Here we hypothesized that ANP may be implicated in mitochondrial uncoupling in the cortical collecting ducts (CCD), affecting sodium transport in this segment.MethodsMouse cortical collecting duct (mpkCCD) cells were cultured in DMEM/F12 medium with supplements and grown on glass‐bottom dishes, 96‐well plates or permeable supports. Cells were treated with ANP (5 nM to 10 μM range) for 1 or 24 hours. Fluorescent dyes TMRM and Rhod123, CellRox Deep Red, AmplexRed, Rhod2 and Hoechst 33342 were used to label mitochondrial membrane potential (TMRM/Rhod123), production of mitochondrial ROS, hydrogen peroxide, calcium, and nuclei in live cells, respectively. A Leica TCS SP5 confocal microscope or a BMG Labtech microplate reader were employed to monitor fluorescence intensity changes in response to ANP. Mitochondrial stress test assays were performed using a Seahorse XF96 Extracellular Flux Analyzer. Sodium currents in the polarized mpkCCD monolayers were measured with an EVOM multimeter. One‐way ANOVA (OriginPro) was used for statistical comparisons.ResultsFluorescence microscopy with TMRM showed a mild (~30% at maximum effect) dose‐dependent decrease in mitochondrial membrane potential in mpkCCD cells treated with low dose ANP for 1, 2 and 24 h (1 nM to 500 nM), which was, interestingly, attenuated by higher ANP concentrations (>5 μM). These data were confirmed in a 96‐well plate assay using Rhod 123 (1 h and 24 hours). In addition, we observed an acute increase in ROS (and specifically, hydrogen peroxide) production and mitochondrial Ca2+ level in response to ANP (at 1 h), which is in line with the mild uncoupling reported above. Preliminary seahorse analysis indicated that ANP decreases mitochondrial respiration in these cells in a dose‐dependent manner. We have also shown that direct uncoupling of mitochondria with FCCP results in a dose‐dependent decrease in sodium currents mediated by Epithelial Sodium Channel (ENaC) as measured in short circuit current experiments.ConclusionDecreased mitochondrial membrane potential is indicative of a disruption in the oxidative phosphorylation, which is the main mechanism of ATP synthesis in the cell and the source of energy for Na+/K+‐ATPase (NKA). Since NKA provides the gradient for Na+ reabsorption in CCD, the reported mitochondria‐mediated effect suggests a novel pathway through which ANP may regulate Na+ reabsorption in the collecting ducts, potentially affecting blood pressure.Support or Funding InformationAPS Summer Undergraduate Fellowship Program; NIH R00 DK105160, Dialysis Clinic Inc Reserve Funds.

Effects of Selective Agonists of V1a, V2, and V1b Receptors on Sodium Transport in Rat Kidney.

The role of subtypes of vasopressin receptors in modulation of renal sodium reabsorption was studied in in vivo experiments on Wistar rats. Selective V1a receptor agonist reduced sodium reabsorption in the kidneys and expression of these receptors increased by practically 100 times. This effect was similar to the effect of furosemide. Selective V2 receptor agonist enhanced sodium reabsorption in the kidney and simultaneously increased reabsorption of solute-free water. Stimulation of V1b receptors did not affect sodium transport. Our findings attest to the key role of V1a receptors in the regulation of renal excretion of sodium ions.

Effects of the vasopressin agonist terlipressin on plasma cAMP and ENaC excretion in the urine in patients with cirrhosis and water retention

Background. Terlipressin is a vasopressin analogue used for its potent V1a effects in cirrhotic patients. Recent data suggest that terlipressin has affinity to renal V2 receptors and modulates Aquaporin 2 (AQP2) expression and free water clearance. Stimulation of renal V2 receptors may also affect sodium transport via the Epithelial Sodium Channel (ENaC). Furthermore, endothelial V2 receptors may indirectly affect proximal sodium handling by increasing plasma cAMP. Methods. We investigated 18 patients with cirrhosis and ascites before and after infusion of 2 mg of terlipressin. Plasma cAMP and urine AQP2 were measured and a newly developed radioimmunoassay was used to quantify ENaC in the urine. Results. Mean arterial blood pressure increased from 87 ± 15 to 105 ± 19 mmHg, p < 0.001 after terlipressin infusion and GFR increased from 52 ± 6 to 69 ± 9 mL/min, p < 0.01. Urine-ENaC in ng/mmol creatinine increased from 42 ± 6 to 50 ± 7 ng/mmol creatinine, p = 0.05. Urine sodium increased from 43 ± 8 to 62 ± 9 mmol/L, p < 0.01. Plasma cAMP was not affected by terlipressin, 106 (63–673) vs. 103.5 (69–774) pmol/mL, NS. The rise in ENaC excretion correlated with the rise in AQP2 excretion, r = 0.63, p < 0.01. There was a weak correlation between the change in MAP and the rise in AQP2 excretion (p < 0.05). Conclusions. Increased ENaC excretion suggests increased abundance of ENaC and resultant increased distal sodium reabsorption. The V2 effects of terlipressin are insufficient to stimulate the endothelial V2 receptors since plasma cAMP is unaltered. Despite pronounced V1a and some V2 effects of terlipressin, additional effects on proximal sodium handling are therefore not likely.

Ocular Adverse Effects of Common Psychotropic Agents

All psychotropic medications have the potential to induce numerous and diverse unwanted ocular effects. Visual adverse effects can be divided into seven major categories: eyelid and keratoconjunctival disorders; uveal tract disorders; accommodation interference; angle-closure glaucoma; cataract/pigmentary deposits in the lens and cornea; retinopathy; and other disorders. The disorders of the eyelid and of the keratoconjunctiva are mainly related to phenothiazines and lithium. Chlorpromazine, at high dosages, can commonly cause abnormal pigmentation of the eyelids, interpalpebral conjunctiva and cornea. It can also cause a more worrisome but rarer visual impairment, namely corneal oedema. Lithium can rarely lead to a bothersome eye irritation by affecting sodium transport. Uveal tract problems are mainly associated with tricyclic antidepressants (TCAs), typical antipsychotics, topiramate and selective serotonin reuptake inhibitors (SSRIs). TCAs, typical antipsychotics and SSRIs can all cause mydriasis that is often transient and with no major consequences, but that can promote closure of angles in susceptible patients. Topiramate has been frequently associated with a number of significant ocular symptoms including acquired myopia and angle-closure glaucoma. Problems with accommodation are related to TCAs and to low-potency antipsychotics. TCAs cause transient blurred vision in up to one-third of patients. Angle-closure glaucoma is a serious condition that has been mainly associated with TCAs, low-potency antipsychotics, topiramate and, to a lesser extent, SSRIs. When patients with narrow angles are given TCAs, they all appear to experience induction of glaucomatous attacks. Antipsychotics and SSRIs may lead to an added risk of developing angle-closure glaucoma, but only in predisposed eyes. Topiramate can lead to an allergic-type reaction whereby structures of the lens and ciliary body are displaced, which results in angle-closure glaucoma. Cataractous changes can result from antipsychotics, mainly from high dosages of chlorpromazine or thioridazine. These two drugs, when used at high dosages and for prolonged periods, frequently cause lenticular opacifications. Retinopathy has been shown to be related to high dosages of typical antipsychotics, mainly chlorpromazine and thioridazine. The frequency of occurrence of retinal effects seems to be proportional to the total amount of drug used over a long period of time. Other visual problems of special concern are the ocular dystonias, other eye movement disorders, and decreased ability to perceive colours and to discriminate contrast. Ocular dystonias can occur with antipsychotics (especially high-potency ones), carbamazepine (especially in polytherapy), topiramate and, rarely, with SSRIs. Disturbance in various eye movements is frequently seen with benzodiazepines, antiepileptic drugs and lithium. Impairment in the perception of colours and the discrimination of contrasts has been shown to occur not uncommonly with carbamazepine and lorazepam. Thus, typical antipsychotics, TCAs, lithium, benzodiazepines, carbamazepine, topiramate and SSRIs appear to produce most of the currently recognized ocular problems. Psychiatrists, ophthalmologists and patients need to be aware of and prepared for any medication-induced adverse effect. Early prevention and intervention can avoid most of the serious and potentially irreversible ocular toxicities.

Colfibrate attenuates blood pressure and sodium retention in DOCA-salt hypertension

Clofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR alpha) agonist, increases renal tubular cytochrome P450 4a (Cyp4a) expression thereby increasing 20-hydroxyeicosatetraenoic acid (20-HETE) production. To determine if clofibrate affects blood pressure regulation we studied mice with DOCA-salt induced hypertension in wild-type and PPAR alpha knockout mice. Wild-type mice treated with DOCA-salt had higher mean arterial pressures and higher cumulative sodium balance, but lower renal 20-HETE production than did vehicle-treated mice. Treating DOCA-salt mice with clofibrate attenuated the increase in mean arterial pressure and cumulative sodium balance while increasing 20-HETE production and renal Cyp4a expression. In contrast the PPAR alpha knockout mice treated with clofibrate and DOCA-salt showed no attenuation in the increase of blood pressure, cumulative sodium balance, renal 20-HETE production or Cyp4a protein expression. Expression of the PPAR alpha protein was greater in proximal tubules than in renal microvessels. Our results show that PPAR alpha pathway induces renal tubular 20-HETE production which affects sodium retention and blood pressure regulation in DOCA-salt-treated mice.

The antiepileptic drug phenytoin affects sodium transport in toad epithelium

The effects of phenytoin on isolated Pleurodema thaul toad skin were investigated. Low (micromolar) concentrations of the antiepileptic agent applied to the outside surface of the toad epithelium increased the electrical parameters (short-circuit current and potential difference) by over 40%, reflecting stimulation of Na+ transport, whereas higher (millimolar concentrations, outside and inside surface) decreased both electric parameters, the effect being greater at the inside surface (40% and 80% decrease, respectively). The amiloride test showed that the stimulatory effect was accompanied by an increase and the inhibitory effect by a decrease in the sodium electromotive force (ENa). It is concluded that the drug interaction with membrane lipid bilayers might result in a distortion of the lipid–protein interface contributing to disturbance of Na+ epithelial channel activity. After applying the Na+–K+-ATPase blocker ouabain and replacing the Na+ ions in the outer Ringer's solution by choline, it was concluded that both active and passive transport are involved in sodium absorption, although active transport predominates.

Rat Strain Effects of AT 1 Receptor Activation on D 1 Dopamine Receptors in Immortalized Renal Proximal Tubule Cells

The dopaminergic and renin-angiotensin systems regulate blood pressure, in part, by affecting sodium transport in renal proximal tubules (RPTs). We have reported that activation of a D1-like receptor decreases AT1 receptor expression in the mouse kidney and in immortalized RPT cells from Wistar-Kyoto (WKY) rats. The current studies were designed to test the hypothesis that activation of the AT1 receptor can also regulate the D1 receptor in RPT cells, and this regulation is aberrant in spontaneously hypertensive rats (SHRs). Long-term (24 hours) stimulation of RPT cells with angiotensin II, via AT1 receptors increased total cellular D1 receptor protein in a time- and concentration-dependent manner in WKY but not in SHR cells. Short-term stimulation (15 minutes) with angiotensin II did not affect total cellular D1 receptor protein in either rat strain. However, in the short-term experiments, angiotensin II decreased cell surface membrane D1 receptor protein in WKY but not in SHR cells. D1 and AT1 receptors colocalized (confocal microscopy) and their coimmunoprecipitation was greater in WKY than in SHRs. However, AT1/D1 receptor coimmunoprecipitation was decreased by angiotensin II (10(-8) M/24 hours) to a similar extent in WKY (-22+/-8%) and SHRs (-22+/-12%). In summary, these studies show that AT1 and D1 receptors interact differently in RPT cells from WKY and SHRs. It is possible that an angiotensin II-mediated increase in D1 receptors and dissociation of AT1 from D1 receptors serve to counter regulate the long-term action of angiotensin II in WKY rats; different effects are seen in SHRs.

Aberrant ETB receptor regulation of AT1 receptors in immortalized renal proximal tubule cells of spontaneously hypertensive rats

The renin-angiotensin and endothelin systems interact to regulate blood pressure, in part, by affecting sodium transport in the kidney. Because angiotensin II type 1 (AT(1)) receptor activation increases ETB receptor expression in renal proximal tubule cells from Wistar-Kyoto (WKY) rat, we hypothesize that ETB receptor activation may also regulate AT(1) receptor expression. Furthermore, ETB receptor regulation of the AT(1) receptor may be different in the WKY and spontaneously hypertensive rat (SHR). AT(1) and ETB receptors were studied in immortalized renal proximal tubule cells from WKY and SHRs, using immunoblotting, confocal microscopic colocalization, and immunoprecipitation. In WKY renal proximal tubule cells, an ETB receptor agonist, BQ3020, decreased AT(1) receptor protein in a time- and concentration-dependent manner [median effective concentration (EC(50)) = 3.2 x 10(-10) mol/L, t(1/2)= 15 hours]. The inhibitory effect of BQ3020 (10(-8) mol/L/24 hours) on AT(1) receptor protein was blocked by an ETB receptor antagonist (BQ788). However, BQ3020 (10(-8) mol/L/24 hours) increased ETB receptor protein in WKY renal proximal tubule cells. In contrast, in SHR renal proximal tubule cells, BQ3020 (10(-8) mol/L/24 hours) no longer affected AT(1) or ETB receptor protein. AT(1)/ETB receptors colocalized and coimmunoprecipitated in WKY and SHRs. BQ3020 (10(-8) mol/L/15 minutes) treatment had no effect on AT(1)/ETB coimmunoprecipitation in WKY but decreased it in SHRs. BQ3020 (10(-8) mol/L/15 minutes) treatment increased AT(1) receptor phosphorylation in WKY, but decreased it in SHRs. ETB receptors regulate AT(1) receptors by direct physical receptor interaction and receptor expression. An impaired ETB receptor regulation of the AT(1) receptor may participate in the pathogenesis of high blood pressure in the SHR.

Inhibition of chloride secretion in human bronchial epithelial cells by cigarette smoke extract

Chronic bronchitis, a disease mainly of cigarette smokers, shares many clinical features with cystic fibrosis, a disease of altered ion transport, suggesting that the negative effects of cigarette smoke on mucociliary clearance may be mediated through alterations in ion transport. We tested the hypothesis that cigarette smoke extract would inhibit chloride secretion in human bronchial epithelial cells. In agreement with studies in canine trachea, cigarette smoke extract inhibited net chloride secretion without affecting sodium transport. We performed microelectrode impalements and impedance analysis studies to investigate the physiological mechanisms of this inhibition. These data demonstrated that cigarette smoke extract caused an acute increase in membrane resistances in conjunction with apical membrane hyperpolarization, an effect consistent with inhibition of an apical membrane anion conductance. After this acute phase, both membrane resistances decreased while membrane potentials continued to hyperpolarize, indicating that cigarette smoke extract also inhibited the basolateral entry of chloride into the cell. Furthermore, cigarette smoke extract caused an increase in mucin secretion. Therefore, the ion transport phenotype of human bronchial epithelial cells exposed to cigarette smoke extract is similar to that of cystic fibrosis epithelia in which there is sodium absorption out of proportion to chloride secretion in the setting of increased mucus secretion.

Regulation of the epithelial sodium channel by accessory proteins.

The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. This is clearly demonstrated by rare genetic disorders of sodium-channel activity (Liddle's syndrome and pseudohypoaldosteronism type 1), associated with contrasting effects on blood pressure. The mineralocorticoid aldosterone is a well-established modulator of sodium-channel activity. Considerable insight has now been gained into the intracellular signalling pathways linking aldosterone-mediated changes in gene transcription with changes in ion transport. Activating pathways include aldosterone-induced proteins and especially the serum- and glucocorticoid-inducible kinase (SGK) and the small G-protein, K-Ras 2A. Targeting of the ENaC for endocytosis and degradation is now emerging as a major mechanism for the down-regulation of channel activity. Several proteins acting in concert are an intrinsic part of this process but Nedd4 (neural precursor cell expressed developmentally down-regulated 4) is of central importance. Other mechanisms known to interact with ENaC and affect sodium transport include channel-activating protease 1 (CAP-1), a membrane-anchored protein, and the cystic fibrosis transmembrane regulator. The implications of research on accessory factors controlling ENaC activity are wide-ranging. Understanding cellular mechanisms controlling ENaC activity may provide a more detailed insight not only of ion-channel abnormalities in cystic fibrosis but also of the link between abnormal renal sodium transport and essential hypertension.

A Quantitative Trait Locus for Sodium-Lithium Countertransport Is Linked to Chromosome Four in Baboons

P134 Alterations in cell sodium transport characteristics, such as red blood cell intracellular sodium (ICNa) levels and sodium-lithium countertransport (SLC), are secondary biochemical indices of a primary cell membrane abnormality that have been associated with some forms of essential hypertension. We are studying the effects of genes and environmental factors on hypertension and blood pressure-related phenotypes such as ICNa and SLC in baboons, a non-human primate model for blood pressure regulation. In a previous study of 84 baboons, systolic blood pressure increased with increasing ICNa (p = 0.002) and SLC (p = 0.06). In the current study, genotypes for 280 microsatellite loci, as well as SLC and ICNa data, were determined for 623 baboons comprising 11 pedigrees. The heritabilities of ICNa and SLC were 0.80±0.07 and 0.61±0.10, respectively. We performed a genome screen using a maximum-likelihood based, variance components linkage analysis program (SOLAR) and obtained evidence that a possible quantitative trait locus (QTL) for SLC is located on the baboon homologue of human chromosome 4 between D4S2456 and D4S2365 with a maximum multipoint lod-score = 8.76 (p -10 ) at D4S1645. This QTL accounts for approximately 2/3 of the additive genetic variation in SLC in baboons. We found no evidence for linkage with ICNa. Thus, we have evidence that a gene located on human chromosome 4 (baboon chromosome 5) affects cell sodium transport in baboons. No strong candidate genes have yet been identified in this region. However, future studies to identify and characterize this gene may elucidate fundamental processes that contribute to the development of hypertension.

Glomerular ultrafiltration of IGF-I may contribute to increased renal sodium retention in diabetic nephropathy

Insulin-like growth factor-I (IGF-I) is found in plasma at relatively high levels (∼40 nmol/L) but <1% is present in the free form and >99% is bound to specific binding proteins to form high-molecular-weight complexes of ∼50 and ∼150 kd. We hypothesized that in rats with diabetic nephropathy but not in normal animals, IGF-I-containing binding protein complexes undergo glomerular ultrafiltration, allowing the peptide to interact with IGF-I receptors in apical tubular membranes. By this route, ultrafiltered IGF-I may increase tubular epithelial cell sodium absorption in overt diabetic nephropathy. In serum samples from diabetic rats, IGF-I levels (227 ± 34 ng/mL) were reduced as compared with control levels (319 ± ng/mL, P = .05), and IGF-binding protein-2 (IGFBP-2) is increased about 2-fold. In diabetic rats, IGF-I undergoes glomerular ultrafiltration and is present in proximal tubular fluid that was collected by nephron micropuncture at 2.54 ± 0.54 nmol/L but is below the detection limit in tubular fluid from normal rats. IGFBP-1, IGFBP-2, IGFBP-3, and IGFBP-4 are all present in diabetic rat glomerular ultrafiltrate, but IGFBP-2 levels are greater than those of each of the other three IGFBPs. Neither recombinant human IGF-I (1 nmol/L) nor diabetic rat glomerular ultrafiltrate affect sodium transport in cultured mouse proximal tubular cells. In contrast, rhIGF-I and diabetic rat glomerular ultrafiltrate increase the apical-to-basolateral transport of 22Na+ in distal tubule-like A6 cells through mechanisms involving apical IGF-I receptors. In normal rats, luminal infusion with rhIGF-I or with diabetic rat glomerular ultrafiltrate into late proximal tubules increases distal tubular Na+ absorption. These findings indicate that diabetic glomerular sclerosis causes glomerular ultrafiltration of IGF-I, and they suggest that tubular fluid IGF-I may contribute to sodium (and fluid) retention that is commonly observed in patients with severe diabetic nephropathy.

Characterization of rabbit kidney and brain pancreatic polypeptide-binding neuropeptide Y receptors: differences with Y 1 and Y 2 sites in sensitivity to amiloride derivatives affecting sodium transport

Sites sensitive to human and rat pancreatic polypeptides (hPP and rPP) accounted for more than 30% of the specific binding of [ 125I](Leu 31,Pro 34) human peptide YY (LP-PYY) in particulates from rabbit kidney cortex, and about 10% of the specific binding in membranes from rabbit hypothalamus. The binding of [ 125I]hPP or [ 125I]rPP showed a high-affinity displacement with either hPP, rPP, LP-PYY, neuropeptide Y or peptide YY (K i below 50 pM for all), while being quite insensitive to Y 2-selective ligands. The PP binding had a high sensitivity to alkali cations and inhibitors of phospholipase C, very similar to that of LP-PYY binding ‘masked’ by excess cold hPP. However, as different from the Y 1-like LP-PYY binding, but similar to the binding of the Y 2-selective ligand [ 125I] human peptide YY(3–36) (hPYY(3–36)), the PP binding showed a low sensitivity to guanosine polyphosphates. The PP binding was much more sensitive to N5-substituted amiloride inhibitors of Na + transport than the binding of LP-PYY, or that of hPYY(3–36). The inhibition of PP binding by N5-substituted amilorides was not enhanced by guanine nucleotides or by phospholipase C blockers. However, pairing of N5-substituted amilorides disproportionately increased the inhibition of hPP binding. Thus, in rabbit kidney or hypothalamus, the high-affinity PP-responding sites share some of the basic properties of the Y 1 and Y 2 sites, but are distinguished from both by a high sensitivity to compounds affecting sodium transport. These PP/NPY receptors could associate with membrane structures involved in the control of ion balance and osmotic responses.

Sodium pump and Na +/H + activities in uremic erythrocytes. A microcalorimetric and pH-metric study

The sodium pump and Na +/H + antiport activities in red blood cells from uremic hemodialyzed patients were measured concomitantly. The patients selected ( n = 35) were normotensive and free of intercurrent illness known to affect Na transport. The Na pump activity of intact red blood cells in suspension in their own plasma was measured by flow microcalorimetry. The Na +/H + antiport activity of the erythrocytes from the same patients was determined by a titrimetric technique. The mean global value of the sodium pump was lower in uremics than in controls (13.3 ± 0.6 vs. 11.3 ± 0.8 mW/1 cells, P < 0.05). The Na +/H + antiport maximal activity was decreased in uremics (2.9 ± 0.3 vs. 4.6 ± 0.5 mmol H +/1 cells/h, P < 0.05). Our results thus confirm that uremia per se can affect sodium transport. Moreover it has been shown that a decrease in Na +/H + antiport activity is able to counteract an impairment of sodium pump. The decrease found in this study could thus explain, at least in part, the absence of hypertension in the patients studied despite their decreased sodium pump activity.

La cure laparoscopique du reflux gastro-oesophagien chez l'enfant

The possible role of progressive methylation of phosphatidylethanolamine to phosphatidylcholine on sodium transport was examined in a suspension of rabbit proximal convoluted tubules. The relation between progressive methylation and the action of parathyroid hormone on sodium transport in this nephron segment was also determined. Incubation of the suspended tubules for 10 minutes at 37°C with 200 uM S-adenosyl-L-[3H]-methyl methionine, a methyl donor, revealed a significant rate of de-novo phosphatidylcholine synthesis. The inactive adenosine analogue, 3-deazaadenosine (DZA), had a significant inhibitory effect on lipid methylation. Despite the inhibition of methylation by DZA, the ouabain sensitive component of oxygen consumption, an index of sodium transport, was not affected. PTH significantly inhibited ouabain sensitive oxygen consumption but had no effect on the methylation of phosphatidylethanolamine. Inhibition of methylation by DZA, did not affect the inhibitory effect of PTH on oxygen consumption. These studies demonstrate that in the proximal convoluted tubule of the rabbit the progressive methylation pathway is present and that inhibition of this pathway does not affect sodium transport. In addition, these studies suggest that the inhibitory effect of PTH on sodium transport is not mediated by the methylation pathway.

Evidence for multiple genes determining sodium transport

Sodium transport comprises a set of interacting systems. Consequently, a defective sodium transport gene affects multiple sodium transport systems, and a sodium transport variable measured on a sample of individuals reflects genetic variation from a number of different genes, complicating the task of identifying the effect of a single gene. To test for genes which affect sodium transport, we first applied principal components analysis to 14 variables related to sodium transport, thereby defining uncorrelated sources of variation in the variables. The sample consisted of 1,218 members of 68 pedigrees ascertained through probands with early-onset stroke, hypertension, or coronary heart disease. Segregation analysis of the 14 principal components scores provided evidence for 8 genetic variants which alter sodium transport. One of the 8 variants is recessive, has homozygous genotype frequency estimated as 8.8% of the population, and increases sodium-lithium countertransport, the passive sodium leak, body mass index, and triglyceride; the genetic variant may coincide with an insulin resistance gene. A second of the 8 variants is also recessive, has homozygous genotype frequency estimated as 7.4% of the population, and increases intraerythrocytic sodium and the passive sodium leak while decreasing sodium pump number; the genetic variant may reduce pump number. Two of the 8 variants substantially increase sodium-lithium countertransport; frequency estimates for heterozygotes for the dominant variant and homozygotes for the recessive variant equal 1.8% and 3.1%, respectively. Another of the 8 variants is recessive, has homozygous genotype frequency estimated as 1.9%, and increases body mass index. Each of the 3 remaining variants is rare and expressed in less than 1% of the sample.

Arginine vasopressin and atrial natriuretic peptide do not alter ion transport by cultured fetal distal lung epithelium.

Previous studies have shown that i.v. arginine vasopressin (AVP) decreases but does not stop lung fluid secretion in term fetuses not in labor. Although it has been presumed that the response to AVP results from augmented sodium transport, there is controversy whether AVP actually does affect sodium transport in mammalian lung epithelium. To determine if AVP or aldosterone could alone or together augment sodium transport in the perinatal lung, we studied primary cultures of fetal rat distal lung epithelium in Ussing chambers. The short circuit current of these sodium-transporting cells was not affected by the application of either 30 or 300 mU/mL AVP whether or not they were previously exposed to aldosterone (10(-6) M). Aldosterone also did not affect the baseline bioelectric properties. Short circuit current increased in response to 8-bromo cAMP (10(-4) M) and 3-isobutyl-1-methylxanthine (10(-3) M) to levels 169 +/- 16 (SEM) and 172 +/- 7% of respective baseline values. AVP had no effect in cells pretreated with 3-isobutyl-1-methylxanthine. Monolayers also did not respond to atrial natriuretic peptide (10(-11) to 10(-8) M). Monolayers of Na-absorbing A6 renal epithelium did increase short circuit current with either aldosterone or AVP. AVP increased endogenous cAMP levels in A6 but not fetal rat distal lung epithelium cells, suggesting that fetal rat distal lung epithelium lacks V2 receptors. These studies demonstrate that AVP does not increase ion transport in cultured fetal distal lung epithelium although these cells possess the necessary second messenger system.

Effect of calcium on blood pressure, platelet aggregation and erythrocyte sodium transport in Dahl salt-sensitive rats

Forty 11-week-old Dahl salt-sensitive rats were divided into four groups matched for blood pressure and weight. Group I was given a sodium-deficient diet, group II a sodium-enriched diet, group III a sodium-enriched diet plus a calcium supplement and group IV a sodium-enriched diet plus nitrendipine, a calcium antagonist. For the first 18 weeks, when the sodium-enriched diet contained 2.6% sodium, there were no differences in blood pressure between the groups; the sodium content was then increased to 8%, and the diets continued for 12 more weeks. At 41 weeks old, the rats in group II had significantly (P less than 0.05) higher systolic blood pressures than the other groups. Erythrocytes from the rats on the low-sodium diet had significantly (P less than 0.025) lower intracellular sodium (3.9 +/- 0.4 mmol/l) while cells from the rats given nitrendipine had significantly (P less than 0.005) higher intracellular sodium (13.3 +/- 0.8 mmol/l) than those from the rats on a high-salt diet (7.4 +/- 1.4 mmol/l). Nitrendipine caused significant (P less than 0.05) decreases in both ouabain-sensitive and furosemide-sensitive sodium efflux. Platelet aggregation in response to 2 mumol/l adenosine diphosphate was not significantly affected by the nitrendipine. The evidence that nitrendipine markedly affects sodium transport supports the hypothesis that an interaction of calcium and sodium may be involved in blood pressure control.