Versatility of NaCl transport mechanisms in the cortical collecting duct

Versatility of NaCl transport mechanisms in the cortical collecting duct. Am J Physiol Renal Physiol 313: F1254 –F1263, 2017. First published September 6, 2017; doi:10.1152/ajprenal.00369.2017.—The cortical collecting duct (CCD) forms part of the aldosterone-sensitive distal nephron and plays an essential role in maintaining the NaCl balance and acid-base status. The CCD epithelium comprises principal cells as well as different types of intercalated cells. Until recently, transcellular Na transport was thought to be restricted to principal cells, whereas (acid-secreting) type A and (bicarbonate-secreting) type B intercalated cells were associated with the regulation of acid-base homeostasis. This review describes how this traditional view has been upended by several discoveries in the past decade. A series of studies has shown that type B intercalated cells can mediate electroneutral NaCl reabsorption by a mechanism involving Na-dependent and Na-independent Cl/HCO3 exchange, and that is energetically driven by basolateral vacuolar H-ATPase pumps. Other research indicates that type A intercalated cells can mediate NaCl secretion, through a bumetanide-sensitive pathway that is energized by apical H,K-ATPase type 2 pumps operating as Na/K exchangers. We also review recent findings on the contribution of the paracellular route to NaCl transport in the CCD. Last, we describe cross-talk processes, by which one CCD cell type impacts Na/Cl transport in another cell type. The mechanisms that have been identified to date demonstrate clearly the interdependence of NaCl and acid-base transport systems in the CCD. They also highlight the remarkable versatility of this nephron segment.This work was supported in part by recurring grants from the Institut National de la Sante et de la Recherche Medicale (INSERM), the Centre National de la Recherche Scientifique (CNRS), and the University Pierre et Marie Curie (UPMC). (Institut National de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS); University Pierre et Marie Curie (UPMC))Accepted manuscrip

New insights into sodium transport regulation in the distal nephron: Role of G-protein coupled receptors

International audienceThe renal handling of Na+ balance is a major determinant of the blood pressure (BP) level. The inability of the kidney to excrete the daily load of Na+ represents the primary cause of chronic hypertension. Among the different segments that constitute the nephron, those present in the distal part (i.e., the cortical thick ascending limb, the distal convoluted tubule, the connecting and collecting tubules) play a central role in the fine-tuning of renal Na+ excretion and are the target of many different regulatory processes that modulate Na+ retention more or less efficiently. G-protein coupled receptors (GPCRs) are crucially involved in this regulation and could represent efficient pharmacological targets to control BP levels. In this review, we describe both classical and novel GPCR-dependent regulatory systems that have been shown to modulate renal Na+ absorption in the distal nephron. In addition to the multiplicity of the GPCR that regulate Na+ excretion, this review also highlights the complexity of these different pathways, and the connections between them

H,K-ATPase type 2 contributes to salt-sensitive hypertension induced by K(+) restriction.

In industrialized countries, a large part of the population is daily exposed to low K(+) intake, a situation correlated with the development of salt-sensitive hypertension. Among many processes, adaptation to K(+)-restriction involves the stimulation of H,K-ATPase type 2 (HKA2) in the kidney and colon and, in this study, we have investigated whether HKA2 also contributes to the determination of blood pressure (BP). By using wild-type (WT) and HKA2-null mice (HKA2 KO), we showed that after 4 days of K(+) restriction, WT remain normokalemic and normotensive (112 ± 3 mmHg) whereas HKA2 KO mice exhibit hypokalemia and hypotension (104 ± 2 mmHg). The decrease of BP in HKA2 KO is due to the absence of NaCl-cotransporter (NCC) stimulation, leading to renal loss of salt and decreased extracellular volume (by 20 %). These effects are likely related to the renal resistance to vasopressin observed in HKA2 KO that may be explained, in part by the increased production of prostaglandin E2 (PGE2). In WT, the stimulation of NCC induced by K(+)-restriction is responsible for the elevation in BP when salt intake increases, an effect blunted in HKA2-null mice. The presence of an activated HKA2 is therefore required to limit the decrease in plasma [K(+)] but also contributes to the development of salt-sensitive hypertension

Expression Profile of Nuclear Receptors along Male Mouse Nephron Segments Reveals a Link between ERRβ and Thick Ascending Limb Function

The nuclear receptor family orchestrates many functions related to reproduction, development, metabolism, and adaptation to the circadian cycle. The majority of these receptors are expressed in the kidney, but their exact quantitative localization in this ultrastructured organ remains poorly described, making it difficult to elucidate the renal function of these receptors. In this report, using quantitative PCR on microdissected mouse renal tubules, we established a detailed quantitative expression map of nuclear receptors along the nephron. This map can serve to identify nuclear receptors with specific localization. Thus, we unexpectedly found that the estrogen-related receptor β (ERRβ) is expressed predominantly in the thick ascending limb (TAL) and, to a much lesser extent, in the distal convoluted tubules. In vivo treatment with an ERR inverse agonist (diethylstilbestrol) showed a link between this receptor family and the expression of the Na+,K+-2Cl− cotransporter type 2 (NKCC2), and resulted in phenotype presenting some similarities with the Bartter syndrom (hypokalemia, urinary Na+ loss and volume contraction). Conversely, stimulation of ERRβ with a selective agonist (GSK4716) in a TAL cell line stimulated NKCC2 expression. All together, these results provide broad information regarding the renal expression of all members of the nuclear receptor family and have allowed us to identify a new regulator of ion transport in the TAL segments

CARACTERISATIONS FONCTIONNELLE ET PHARMACOLOGIQUE DES ISOZYMES DE L'ATPASE NA +/K + HUMAINE

L'ATPASE NA +/K + (NKA) EST CONSTITUEE DE DEUX SOUS-UNITES ( ET ) POUR LESQUELLES IL EXISTE PLUSIEURS ISOFORMES (1 A 4 ET 1 A 3). A PRIORI, TOUTES LES ISOFORMES ET SONT CAPABLES DE S'ASSOCIER POUR FORMER UNE ENZYME ACTIVE. LA VARIETE DE COMPLEXES , AINSI QUE LA DISTRIBUTION TISSULAIRE DE CERTAINES ISOFORMES SUGGERENT QUE CES COMPLEXES PEUVENT AVOIR DES CARACTERISTIQUES FONCTIONNELLES DIFFERENTES, ADAPTEES A LA CELLULE DANS LESQUELS ILS SONT EXPRIMES. NKA EST AUSSI LE RECEPTEUR SPECIFIQUE DES DIGITALIQUES, COMPOSES INOTROPES UTILISES DEPUIS LONGTEMPS DANS LE TRAITEMENT DE L'INSUFFISANCE CARDIAQUE. DES ETUDES EFFECTUEES PRINCIPALEMENT CHEZ LE RAT ONT MONTRE QUE LES ISOZYMES 2 ET 3 AYANT UNE HAUTE AFFINITE POUR LES DIGITALIQUES ETAIENT RESPONSABLE DES EFFETS INOTROPES ALORS QUE LES EFFETS NEFASTES ETAIENT DUS AUX ISOZYMES 1 (BASSE AFFINITE). CES CONCLUSIONS NE SEMBLENT PAS POUVOIR EXPLIQUER L'EFFET DES DIGITALIQUES CHEZ L'HOMME PUISQUE CES COMPOSES ONT UN INDEX THERAPEUTIQUE TRES ETROIT ET QU'AUCUNE DIFFERENCE IMPORTANTE D'AFFINITE POUR LES DIGITALIQUES N'A ETE OBSERVEE EN UTILISANT DES PREPARATIONS MEMBRANAIRES DE COEUR HUMAIN CONTENANT LES 3 ISOFORMES ET AU MOINS DEUX ISOFORMES . POUR MIEUX COMPRENDRE LE ROLE FONCTIONNEL ET PHARMACOLOGIQUE DE CHAQUE ISOZYME HUMAINE DE NKA NOUS AVONS OBTENU OU CLONE LES ISOFORMES 1, 2, 3, 1, 2 ET 3, PUIS NOUS AVONS EXPRIME LES 9 COMPLEXES DANS LES OOCYTES DE XENOPUS LAEVIS. NOUS AVONS, AINSI, MIS EN EVIDENCE DES DIFFERENCES FONCTIONNELLES MAJEURES (AFFINITE AU K +, AU NA +, DEPENDANCE AU VOLTAGE, TURN-OVER) ENTRE LES ISOZYMES. NOUS AVONS EGALEMENT MONTRE QUE TOUTES LES ISOZYMES POSSEDENT LA MEME AFFINITE POUR LES DIGITALIQUES, CE QUI CONTRASTE AVEC LE MODELE DU RAT, MAIS QUE L'ISOFORME 2 FIXE ET RELACHE LES DIGITALIQUES 10 FOIS PLUS RAPIDEMENT QUE LES AUTRES ISOFORMES. DE PLUS, NOUS AVONS MIS EN EVIDENCE UN EFFET ANTAGONISTE DE LA FIXATION DES DIGITALIQUES PAR LE K + QUI DEPEND DE L'ISOFORME CONSIDEREE.ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Aperçus mécanistes des altérations primaires et secondaires du transport rénal des ions et de l'eau dans le néphron distal

International audienceThe kidneys, by equilibrating the outputs to the inputs, are essential for maintaining constant the volume, pH and electrolyte composition of the internal milieu. Inability to do so, either because of an internal kidney dysfunction (primary alteration) or because some external factors (secondary alteration) would lead to pathologies, more or less severe, leading to modification of these parameters and affecting the functions of other organs. Alterations of the functions of the collecting duct (CD), the most distal part of the nephron, have been extensively studied and have led to a better diagnosis, a better management of the related diseases and the development of therapeutic tools. Thus, dysfunctions of principal cells specific transporters such as ENaC or AQP2 or its receptors (mineralocorticoid or vasopressin receptors) caused by mutations or by compounds present in the environment (lithium, antibiotics…) has been demonstrated in a variety of syndromes (Liddle, pseudohypoaldosteronism type-1, diabetes insipidus…) affecting salt, potassium and water balance. In parallel, studies of specific transporters (H+-ATPase, anion exchanger 1) in intercalated cells as revealed the mechanisms of related tubulopathies like distal renal distal tubular acidosis or Sjögren syndrome.In this review, we will recapitulate the mechanisms of most of the primary and secondary alteration of the ion transport system of the CD to provide a better understanding of these diseases and highlight how a targeted perturbation may affect many different pathways due to the strong crosstalk and entanglements between the different actors (transporters, cell types)

Glucagon actions on the kidney revisited: possible role in potassium homeostasis

International audienceIt is now recognized that the metabolic disorders observed in diabetes are not, or not only due to the lack of insulin or insulin resistance, but also to elevated glucagon secretion. Accordingly, selective glucagon receptor antagonists are now proposed as a novel strategy for the treatment of diabetes. However, besides its metabolic actions, glucagon also influences kidney function. The glucagon receptor is expressed in the thick ascending limb, distal tubule, and collecting duct, and glucagon regulates the transepithelial transport of several solutes in these nephron segments. Moreover, it also influences solute transport in the proximal tubule, possibly by an indirect mechanism. This review summarizes the knowledge accumulated over the last 30 years about the influence of glucagon on the renal handling of electrolytes and urea. It also describes a possible novel role of glucagon in the short-term regulation of potassium homeostasis. Several original findings suggest that pancreatic α-cells may express a “potassium sensor” sensitive to changes in plasma K concentration and could respond by adapting glucagon secretion that, in turn, would regulate urinary K excretion. By their combined actions, glucagon and insulin, working in a combinatory mode, could ensure an independent regulation of both plasma glucose and plasma K concentrations. The results and hypotheses reviewed here suggest that the use of glucagon receptor antagonists for the treatment of diabetes should take into account their potential consequences on electrolyte handling by the kidney

FXYD3 (Mat-8), a New Regulator of Na,K-ATPase

Four of the seven members of the FXYD protein family have been identified as specific regulators of Na,K-ATPase. In this study, we show that FXYD3, also known as Mat-8, is able to associate with and to modify the transport properties of Na,K-ATPase. In addition to this shared function, FXYD3 displays some uncommon characteristics. First, in contrast to other FXYD proteins, which were shown to be type I membrane proteins, FXYD3 may have a second transmembrane-like domain because of the presence of a noncleavable signal peptide. Second, FXYD3 can associate with Na,K- as well as H,K-ATPases when expressed in Xenopus oocytes. However, in situ (stomach), FXYD3 is associated only with Na,K-ATPase because its expression is restricted to mucous cells in which H,K-ATPase is absent. Coexpressed in Xenopus oocytes, FXYD3 modulates the glycosylation processing of the β subunit of X,K-ATPase dependent on the presence of the signal peptide. Finally, FXYD3 decreases both the apparent affinity for Na(+) and K(+) of Na,K-ATPase

The renal cortical collecting duct: a secreting epithelium?

International audienceIn vitro microperfusion experiments have demonstrated that cortical collecting ducts (CCDs) reabsorb sodium via principal and type B intercalated cells under sodium-depleted conditions and thereby contribute to sodium and blood pressure homeostasis. However, these experiments were performed in the absence of the transepithelial ion concentration gradients that prevail in vivo and determine paracellular transport. The present study aimed to characterize Na+, K+ and Cl− fluxes in the mouse CCD in the presence of physiological transepithelial concentration gradients. For this purpose, we combined in vitro measurements of ion fluxes across microperfused CCDs of sodium-depleted mice with the predictions of a mathematical model. When NaCl transport was inhibited in all cells, CCDs secreted Na+ and reabsorbed K+; Cl− transport was negligible. Removing inhibitors of type A and B intercalated cells increased Na+ secretion in wild-type (WT) mice but not in H+/K+-ATPase type 2 (HKA2) knockout mice. Further inhibition of basolateral NaCl entry via the Na+-K+-2Cl− cotransporter in type A intercalated cells reduced Na+ secretion in WT mice to the levels observed in HKA2−/− mice. With no inhibitors, WT mouse CCDs still secreted Na+ and reabsorbed K+. In vivo, HKA2−/− mice excreted less Na+ than WT mice after switching to a high-salt diet. Taken together, our results indicate that type A intercalated cells secrete Na+ via basolateral Na+-K+-2Cl− cotransporters in tandem with apical HKA2 pumps. They also suggest that the CCD can mediate overall Na+ secretion, and that its ability to reabsorb NaCl in vivo depends on the presence of acute regulatory factors

Glucagon revisited : Coordinated actions on the liver and kidney

International audienceGlucagon secretion is stimulated by a low plasma glucose concentration. By activating glycogenolysis and gluconeogenesis in the liver, glucagon contributes to maintain a normal glycemia. Glucagon secretion is also stimulated by the intake of proteins, and glucagon contributes to amino acid metabolism and nitrogen excretion. Amino acids are used for gluconeogenesis and ureagenesis, two metabolic pathways that are closely associated. Intriguingly, cyclic AMP, the second messenger of glucagon action in the liver, is released into the bloodstream becoming an extracellular messenger. These effects depend not only on glucagon itself but on the actual glucagon/insulin ratio because insulin counteracts glucagon action on the liver.This review revisits the role of glucagon in nitrogen metabolism and in disposal of nitrogen wastes. This role involves coordinated actions of glucagon on the liver and kidney. Glucagon influences the transport of fluid and solutes in the distal tubule and collecting duct, and extracellular cAMP influences proximal tubule reabsorption. These combined effects increase the fractional excretion of urea, sodium, potassium and phosphates. Moreover, the simultaneous actions of glucagon and extracellular cAMP are responsible, at least in part, for the protein-induced rise in glomerular filtration rate that contributes to a more efficient excretion of protein-derived end products