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

Dopamine coordinates the effect of natriuretic and antinatriuretic factors

Living organisms are dependent on a precise regulation of water and sodium. The stability of the internal environment is maintained through a series of feedback mechanisms, in response to changes within the organism as well as to changes in the external environment. Many organs in the body participate in sodiumand water turn over, but the kidney is the only organ in the body that excretes or retains sodium and water in a regulated fashion. Salt retention is a risk factor in the development of hypertension which may lead to renal insufficiency, heart failure and cerebrovascular catastrophes. The traditional view has been that hypertension is caused by an excess of factors that produce vasoconstriction and sodium retention. This hypothesis has been modified after reports showing that a low availability of vasodilative, natriuretic factors also predisposes to hypertension. The precision by which sodium balance is regulated suggests an intricate interaction between modulatory factors released from intra‐ and extrarenal sources. Intrarenally produced dopamine has a central role in this interactive network. Dopamine acts as an autocrine and paracrine factor to inhibit the activity of renal tubular Na+, K+‐ATPase as well as of a number of tubular sodium influx pathways. Other natriuretic factors activate the renal dopamine system via a heterologous recruitment of dopamine‐1 like (D1R) to the plasma membrane, whereas dopamine counteracts the effect of antinatriuretic factors via unknown mechanisms. Prolactin regulates fluid transport across the plasma membrane by unknown mechanisms. Prolactin interacts with dopamine in various tissues. Here we report that prolactin induces a dramatic nine fold increase in urinary sodium excretion associated with a decrease in renal proximal tubular Na+, K+‐ATPase activity. These effects were abolished by a D1R antagonist. We found that prolactin signals via similar pathways as D1R in the renal proximal tubules, including protein kinas A, protein kinase C and PI3 kinase activation and that prolactin induced a heterologous recruitment of D1R to the plasma membrane. These results suggest that the renal dopamine system has a permissive role for prolactin. Dopamine acting on the D1 family of receptors, and angiotensin II, acting on AT1 receptors, exert opposite effects on sodium excretion. Recent studies have shown that the AT1 receptor and the D1 receptor form a dimer, where they act as a unit of opposites. Here we report that the power of the AT1 receptor and D1 receptor interaction is increased by the AT1 receptor antagonist losartan. Losartan caused significant increase of the plasma membrane expression of D1 receptors. We conclude that the effect of losartan bound AT1 receptors on D1 receptor plasma membrane expression can be attributed to the function of the AT1 receptor‐ D1 receptor heterodimer. Taken together these results indicate that losartan will, by binding to the AT1 receptor, exert allosteric effects on its protomer, the D1 receptor, resulting in activation of D1 receptor signaling. Allosteric modulation within a heterodimer, where a structural modification in one protomer will affect the structure and function of the other protomer, has been intensively studied in the past decade, and is generally considered to be an important indirect mechanism for control of receptor function. To test the concept of allosteric interaction between the losartan bound AT1 receptor and the D1 receptors in an in vivo model, we compared the antihypertensive effects of losartan alone and with co‐treatment of losartan and a D1 receptor antagonist in rats with experimental hypertension. We found that addition of a D1 receptor antagonist significantly attenuated the antihypertensive effect of losartan. Not only G protein coupled receptors but also a classic tyrosine receptor, the prolactin receptor, exert its saltregulating effect by heterologous recruitment and associated activation of renal D1 receptors. The finding that an AT1R antagonist can activate D1R signaling and that this effect is dependent on AT1 receptor and D1 receptor interaction is a novel finding and has potential pharmacologic implications

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

Properties and expression of Na+/K+-ATPase α-subunit isoforms in the brain of the swamp eel, Monopterus albus, which has unusually high brain ammonia tolerance

10.1371/journal.pone.0084298PLoS ONE812-POLN

Astrocytic transporters in Alzheimer's disease

Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer’s disease. These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease modifying therapies for Alzheimer’s disease, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of Alzheimer’s disease. A small number of the four hundred transporter superfamilies’ are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in Alzheimer’s disease. Here we review the current evidence for six astrocytic transporter subfamilies involved in Alzheimer’s disease, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling Alzheimer’s disease

The non-gastric H,K-ATPase is oligomycin-sensitive and can function as an H+,NH4(+)-ATPase.

Contains fulltext : 48560.pdf (Publisher’s version ) (Open Access)We used the baculovirus/Sf9 expression system to gain new information on the mechanistic properties of the rat non-gastric H,K-ATPase, an enzyme that is implicated in potassium homeostasis. The alpha2-subunit of this enzyme (HKalpha2) required a beta-subunit for ATPase activity thereby showing a clear preference for NaKbeta1 over NaKbeta3 and gastric HKbeta. NH4(+), K+, and Na+ maximally increased the activity of HKalpha2-NaKbeta1 to 24.0, 14.2, and 5.0 micromol P(i) x mg(-1) protein x h(-1), respectively. The enzyme was inhibited by relatively high concentrations of ouabain and SCH 28080, whereas it was potently inhibited by oligomycin. From the phosphorylation level in the presence of oligomycin and the maximal NH4(+)-stimulated ATPase activity, a turnover number of 20,000 min(-1) was determined. All three cations decreased the steady-state phosphorylation level and enhanced the dephosphorylation rate, disfavoring the hypothesis that Na+ can replace H+ as the activating cation. The potency with which vanadate inhibited the cation-activated enzyme decreased in the order K+ > NH4(+) > Na+, indicating that K+ is a stronger E2 promoter than NH4(+), whereas in the presence of Na+ the enzyme is in the E1 form. For K+ and NH4(+), the E2 to E1 conformational equilibrium correlated with their efficacy in the ATPase reaction, indicating that here the transition from E2 to E1 is rate-limiting. Conversely, the low maximal ATPase activity with Na+ is explained by a poor stimulatory effect on the dephosphorylation rate. These data show that NH4(+) can replace K+ with similar affinity but higher efficacy as an extracellular activating cation in rat nongastric H,K-ATPase

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

Surface Charges of the Membrane Crucially Affect Regulation of Na,K-ATPase by Phospholemman (FXYD1)

Abstract The human a1/His10-b1 isoform of Na,K-ATP-ase has been reconstituted as a complex with and without FXYD1 into proteoliposomes of various lipid compositions in order to study the effect of the regulatory subunit on the half-saturating Na? concentration (K1/2) of Na? ions for activation of the ion pump. It has been shown that the fraction of negatively charged lipid in the bilayer crucially affects the regulatory properties. At low concentrations of the nega-tively charged lipid DOPS (\10 %), FXYD1 increases K1/2 of Na? ions for activation of the ion pump. Phosphorylation of FXYD1 by protein kinase A at Ser68 abrogates this effect. Conversely, for proteoliposomes made with high concen-trations of DOPS ([10 %), little or no effect of FXYD1 on theK1/2 ofNa? ions is observed. Depending on ionic strength and lipid composition of the proteoliposomes, FXYD1 can alter the K1/2 of Na? ions by up to twofold. We propose possible molecular mechanisms to explain the regulatory effects of FXYD1 and the influence of charged lipid and protein phosphorylation. In particular, the positively charged C-terminal helix of FXYD1 appears to be highly mobile and may interactwith the cytoplasmicNdomain of thea-subunit, the interaction being strongly affected by phosphorylation at Ser68 and the surface charge of the membrane