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Transport through lipids and aquaporins is osmotic and entirely driven by the difference in osmotic pressure. Water transport in cotransporters and uniporters is different: Water can be cotransported, energized by coupling to the substrate flux by a mechanism closely associated with protein. In the K⁺/Cl⁻ and the Na⁺/K⁺/2Cl⁻ cotransporters, water is entirely cotransported, while water transport in glucose uniporters and Na⁺-coupled transporters of nutrients and neurotransmitters takes place by both osmosis and cotransport. The molecular mechanism behind cotransport of water is not clear. It is associated with the substrate movements in aqueous pathways within the protein; a conventional unstirred layer mechanism can be ruled out, due to high rates of diffusion in the cytoplasm. The physiological roles of the various modes of water transport are reviewed in relation to epithelial transport. Epithelial water transport is energized by the movements of ions, but how the coupling takes place is uncertain. All epithelia can transport water uphill against an osmotic gradient, which is hard to explain by simple osmosis. Furthermore, genetic removal of aquaporins has not given support to osmosis as the exclusive mode of transport. Water cotransport can explain the coupling between ion and water transport, a major fraction of transepithelial water transport and uphill water transport. Aquaporins enhance water transport by utilizing osmotic gradients and cause the osmolarity of the transportate to approach isotonicity.

WNK1 and WNK4 [WNK, with no lysine (K)] are serine-threonine kinases that function as molecular switches, eliciting coordinated effects on diverse ion transport pathways to maintain homeostasis during physiological perturbation. Gain-of-function mutations in either of these genes cause an inherited syndrome featuring hypertension and hyperkalemia due to increased renal NaCl reabsorption and decreased K+secretion. Here, we reveal unique biochemical and functional properties of WNK3, a related member of the WNK kinase family. Unlike WNK1 and WNK4, WNK3 is expressed throughout the nephron, predominantly at intercellular junctions. Because WNK4 is a potent inhibitor of members of the cation-cotransporter SLC12A family, we used coexpression studies in Xenopus oocytes to investigate the effect of WNK3 on NCC and NKCC2, related kidney-specific transporters that mediate apical NaCl reabsorption in the thick ascending limb and distal convoluted tubule, respectively. In contrast to WNK4's inhibitory activity, kinase-active WNK3 is a potent activator of both NKCC2 and NCC-mediated transport. Conversely, in its kinase-inactive state, WNK3 is a potent inhibitor of NKCC2 and NCC activity. WNK3 regulates the activity of these transporters by altering their expression at the plasma membrane. Wild-type WNK3 increases and kinase-inactive WNK3 decreases NKCC2 phosphorylation at Thr-184 and Thr-189, sites required for the vasopressin-mediated plasmalemmal translocation and activation of NKCC2 in vivo. The effects of WNK3 on these transporters and their coexpression in renal epithelia implicate WNK3 in NaCl, water, and blood pressure homeostasis, perhaps via signaling downstream of vasopressin.

Background We found that a mechanism of hypertension in pseudohypoaldosteronism type II (PHAII) caused by a WNK4 missense mutation (D561A) was activation of the WNK-OSR1/SPAK-NCC signal cascade. However, the pathogenic effect of intronic deletions in WNK1 genes also observed in PHAII patients remains unclear. To understand the pathophysiological roles of WNK1 in vivo, WNK1 +/− mice have been analyzed, because homozygous WNK1 knockout is embryonic lethal. Although WNK1 +/− mice have been reported to have hypotension, detailed analyses of the WNK signal cascade in the kidney and other organs of WNK1 +/− mice have not been performed. Method We assess the effect of heterozygous deletion of WNK1 on the WNK-OSR1/SPAK-NCC/NKCC1/NKCC2 signal cascade in the kidney and blood vessels. Results Contrary to the previous report, the blood pressure of WNK1 +/− mice was not decreased, even under a low-salt diet. Under a WNK4 D561A/+ background, the heterozygous deletion of the WNK1 gene did not reduce the high blood pressure either. We then evaluated the phosphorylation status of OSR1, SPAK, NCC, NKCC1, and NKCC2 in the kidney, but no significant decrease in the phosphorylation was observed in WNK1 +/− mice or WNK1 +/− WNK4 D561A/+ mice. In contrast, a significant decrease in NKCC1 phosphorylation in the aorta and a decreased pressure-induced myogenic response in the mesenteric arteries were observed in WNK1 +/− mice. Conclusion The contribution of WNK1 to total WNK kinase activity in the kidney may be small, but that WNK1 may play a substantial role in the regulation of blood pressure in the arteries.

This review summarizes the data on the functioning of carriers providing electroneutral symport of sodium, potassium, and chloride (Na + ,K + ,2Cl − cotransport), potassium and chloride (K + ,Cl − cotransport), and sodium and chloride (K + ,Cl − cotransport) as well as molecular mechanisms of the regulation of these carriers and their physiological significance. We emphasized the involvement of chloride-coupled carriers in the regulation of cell volume and intracellular chloride concentration and novel data on the role of ubiquitous isoform of Na + ,K + ,2Cl − cotransporter NKCC1 in regulation of vascular smooth muscle contraction and activity of GABA A receptors. Finally, we analyzed the data on activation of NKCC1 in patients with essential hypertension and its role in the long-term maintenance of elevated systemic blood pressure and myogenic response in microcirculatory beds.

CONTENTS: Summary 54 I. Introduction 55 II. The role of nonselective cation channels in primary sodium influx - a solid consensus. How solid is the evidence? 55 III. Low-affinity cation transporter 1 - a forgotten link? 61 IV. Are potassium transporters implicated in sodium influx? 62 V. HKT: a saga of twists and turns - where do we stand? 64 VI. SOS: an ambiguous tale 67 VII. Vacuolar storage via NHX: some lingering questions 68 VIII. Other pathways - the apoplast and possibilities of symport with chloride 69 IX. ‘Toxic' Na⁺ fluxes, Na⁺‘homeostasis', and the question of cytosolic Na⁺ 71 X. Concluding remarks 72 Acknowledgements 73 References 73 SUMMARY: Sodium (Na) toxicity is one of the most formidable challenges for crop production world-wide. Nevertheless, despite decades of intensive research, the pathways of Na⁺ entry into the roots of plants under high salinity are still not definitively known. Here, we review critically the current paradigms in this field. In particular, we explore the evidence supporting the role of nonselective cation channels, potassium transporters, and transporters from the HKT family in primary sodium influx into plant roots, and their possible roles elsewhere. We furthermore discuss the evidence for the roles of transporters from the NHX and SOS families in intracellular Na⁺ partitioning and removal from the cytosol of root cells. We also review the literature on the physiology of Na⁺ fluxes and cytosolic Na⁺ concentrations in roots and invite critical interpretation of seminal published data in these areas. The main focus of the review is Na⁺ transport in glycophytes, but reference is made to literature on halophytes where it is essential to the analysis.

Diabetes mellitus is associated with natriuresis, whereas estrogen has been shown to be renoprotective in diabetic nephropathy and may independently regulate renal sodium reabsorption. The aim of this study was to determine the effects of 17-β estradiol (E2) replacement to diabetic, ovariectomized (OVX) female rats on the expression of major renal sodium transporters. Female, Sprague–Dawley rats (210 g) were randomized into four groups: (1) OVX; (2) OVX+E2; (3) diabetic+ovariectomized (D+OVX); and (4) diabetic+ovariectomized+estrogen (D+OVX+E2). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg·body weight (bw)). Rats received phytoestrogen-free diet and water ad libitum for 12 weeks. E2 attenuated hyperglycemia, hyperalbuminuria, and hyperaldosteronism in D rats, as well as the diabetes-induced changes in renal protein abundances for the bumetanide-sensitive Na–K–2Cl cotransporter (NKCC2), and the α- and β-subunits of the epithelial sodium channel (ENaC), that is, E2 decreased NKCC2, but increased α- and β-ENaC abundances. In nondiabetic rats, E2 decreased plasma K+ and increased urine K+/Na+ ratio, as well as decreased the abundance of NKCC2, β-ENaC, and α-1-Na–K–adenosine triphosphate (ATP)ase in the outer medulla. Finally, the diabetic, E2 rats had measurably lower final circulating levels of E2 than the nondiabetic E2 rats, despite an identical replacement protocol, suggesting a shorter biological half-life of E2 with diabetes. Therefore, E2 attenuated diabetes and preserved renal sodium handling and related transporter expression levels. In addition, E2 had diabetes-independent effects on renal electrolyte handling and associated proteins.

Muscle spasticity is a major problem for individuals with SCI. Now, Laurent Vinay and his colleagues report that downregulation of the potassium-chloride cotransporter in spinal cord motor neurons after SCI has a key role in the development of spasticity ( pages 270–271 ). Hyperexcitability of spinal reflexes and reduced synaptic inhibition are commonly associated with spasticity after spinal cord injury (SCI). In adults, the activation of γ-aminobutyric acid A (GABA A ) and glycine receptors inhibits neurons as a result of low intracellular chloride (Cl − ) concentration, which is maintained by the potassium-chloride cotransporter KCC2 (encoded by Slc12a5 ). We show that KCC2 is downregulated after SCI in rats, particularly in motoneuron membranes, thereby depolarizing the Cl − equilibrium potential and reducing the strength of postsynaptic inhibition. Blocking KCC2 in intact rats reduces the rate-dependent depression (RDD) of the Hoffmann reflex, as is observed in spasticity. RDD is also decreased in KCC2-deficient mice and in intact rats after intrathecal brain-derived neurotrophic factor (BDNF) injection, which downregulates KCC2. The early decrease in KCC2 after SCI is prevented by sequestering BDNF at the time of SCI. Conversely, after SCI, BDNF upregulates KCC2 and restores RDD. Our results open new perspectives for the development of therapeutic strategies to alleviate spasticity.

In this article, the authors review the classic, integrative principles of water balance. They use this model to discuss the role of underlying genes and gene products (proteins) in water balance and to provide a mechanistic basis for decisions about related disorders. The hypothalamic–neurohypophyseal–renal axis normally maintains water balance during variations in water intake and nonrenal losses of water. Failure of this mechanism is common in hospitalized patients, and it results in a variety of water-balance disorders. In this article, we begin by reviewing the classic, integrative principles of water balance in mammals and then use this classic model as a framework to discuss the genes and gene products (proteins) involved in water balance. In so doing, our goal is to provide clinicians with a mechanistic basis for decisions regarding the diagnosis and treatment of water-balance disorders. The regulation of water balance . . .

Stressors such as soil salinity and dehydration are major constraints on plant growth, causing worldwide crop losses. Compounding these insults, increasing climate volatility requires adaptation to fluctuating conditions. Salinity stress responses are relatively well understood in Arabidopsis thaliana, making this system suited for the rapid molecular dissection of evolutionary mechanisms. In a large-scale genomic analysis of Catalonian A. thaliana, we resequenced 77 individuals from multiple salinity gradients along the coast and integrated these data with 1,135 worldwide A. thaliana genomes for a detailed understanding of the demographic and evolutionary dynamics of naturally evolved salinity tolerance. This revealed that Catalonian varieties adapted to highly fluctuating soil salinity are not Iberian relicts but instead have immigrated to this region more recently. De novo genome assembly of three allelic variants of the high-affinity K⁺ transporter (HKT1;1) locus resolved structural variation between functionally distinct alleles undergoing fluctuating selection in response to seasonal changes in soil salinity. Plants harboring alleles responsible for low root expression of HKT1;1 and consequently high leaf sodium (HKT1;1HLS ) were migrants that have moved specifically into areas where soil sodium levels fluctuate widely due to geography and rainfall variation. We demonstrate that the proportion of plants harboring HKT1;1HLS alleles correlates with soil sodium level over time, HKT1;1HLS -harboring plants are better adapted to intermediate levels of salinity, and the HKT1;1HLS allele clusters with high-sodium accumulator accessions worldwide. Together, our evidence suggests that HKT1;1 is under fluctuating selection in response to climate volatility and is a worldwide determinant in adaptation to saline conditions.

Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13 C-glucose and in vivo hyperpolarized 13 C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition. Tumor cells can fuel their metabolism with lactate. Here the authors show that inhibition of mitochondrial pyruvate carrier (MPC) blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation and inhibits oxidative metabolism, ultimately resulting in cytotoxicity and radiosensitization.