Electroneutral cation-Cl− cotransporters compose a family of solute carriers in which cation (Na+ or K+) movement through the plasma membrane is always accompanied by Cl− in a 1:1 stoichiometry. Se...

https://www.physiology.org/doi/pdf/10.1152/physrev.00011.2004

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

This review examines epidemiologic, physiological, and molecular evidence that the interplay between sodium and potassium is central to the development of hypertension. The review concludes with recommendations for reducing sodium and increasing potassium in the diet.

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Sodium and Potassium in the Pathogenesis of Hypertension

Renal proximal tubular reabsorption of P(i) is a key element in overall P(i) homeostasis, and it involves a secondary active P(i) transport mechanism. Among the molecularly identified sodium-phosphate (Na/P(i)) cotransport systems a brush-border membrane type IIa Na-P(i) cotransporter is the key player in proximal tubular P(i) reabsorption. Physiological and pathophysiological alterations in renal P(i) reabsorption are related to altered brush-border membrane expression/content of the type IIa Na-P(i) cotransporter. Complex membrane retrieval/insertion mechanisms are involved in modulating transporter content in the brush-border membrane. In a tissue culture model (OK cells) expressing intrinsically the type IIa Na-P(i) cotransporter, the cellular cascades involved in "physiological/pathophysiological" control of P(i) reabsorption have been explored. As this cell model offers a "proximal tubular" environment, it is useful for characterization (in heterologous expression studies) of the cellular/molecular requirements for transport regulation. Finally, the oocyte expression system has permitted a thorough characterization of the transport characteristics and of structure/function relationships. Thus the cloning of the type IIa Na-P(i )cotransporter (in 1993) provided the tools to study renal brush-border membrane Na-P(i) cotransport function/regulation at the cellular/molecular level as well as at the organ level and led to an understanding of cellular mechanisms involved in control of proximal tubular P(i) handling and, thus, of overall P(i) homeostasis.

Proximal Tubular Phosphate Reabsorption: Molecular Mechanisms

Emerging evidence suggests that the intravenous injection of bone marrow-derived stromal cells (BMSC) improves renal function after acute tubular injury, but the mechanism of this effect is controversial. In this article, we confirm that intravenous infusion of male BMSC reduced the severity of cisplatin-induced acute renal failure in adult female mice. This effect was also seen when BMSC (or adipocyte-derived stromal cells (AdSC)), were given by intraperitoneal injection. Infusion of BMSC enhanced tubular cell proliferation after injury and decreased tubular cell apoptosis. Using the Y chromosome as a marker of donor stromal cells, examination of multiple kidney sections at one or four days after cell infusion failed to reveal any examples of stromal cells within the tubules, and only rare examples of stromal cells within the renal interstitium. Furthermore, conditioned media from cultured stromal cells induced migration and proliferation of kidney-derived epithelial cells and significantly diminished cisplatin-induced proximal tubule cell death in vitro. Intraperitoneal administration of this conditioned medium to mice injected with cisplatin diminished tubular cell apoptosis, increased survival, and limited renal injury. Thus, marrow stromal cells protect the kidney from toxic injury by secreting factors that limit apoptosis and enhance proliferation of the endogenous tubular cells, suggesting that transplantation of the cells themselves is not necessary. Identification of the stromal cell-derived protective factors may provide new therapeutic options to explore in humans with acute kidney injury.

Stromal Cells Protect against Acute Tubular Injury via an Endocrine Effect

Tubular reabsorption of filtered sodium is quantitatively the main contribution of kidneys to salt and water homeostasis The transcellular reabsorption of sodium proceeds by a two-step mechanism: 

https://www.physiology.org/doi/pdf/10.1152/physrev.2001.81.1.345

Sodium-Potassium-Adenosinetriphosphatase-Dependent Sodium Transport in the Kidney: Hormonal Control

In addition to the well established action of PTH in proximal tubules and of AVP in collecting tubules, polypeptide hormones were recently shown to regulate transport properties in other tubular portions. Although still scarce, such physiological studies using isolated perfused tubules demonstrated hormonal effects in those nephron segments observed to contain responsive adenylate cyclase and not in the others. Moreover, the same effects were elicited by applying exogenous cAMP or cAMP derivatives. There is, therefore, good evidence that hormone-dependent adenylate cyclase is involved in the cell mechanisms through which many hormones regulate tubular functions. The effects obtained varied depending on the segment of tubule used. It is not yet established whether the nature of the hormonal effect induced via cAMP is entirely specified by the responding cell types or is also specified by the hormone itself. Further studies are needed to clarify this important problem, as well as many other as yet unsolved questions. There is obviously much more to learn about the hormonal regulation of tubular cell functions by using appropriate biochemical and physiological micromethods.

Distribution of hormone-dependent adenylate cyclase in the nephron and its physiological significance.

This study demostrates the existence of an adenylate cyclase sensitive to vasopressin in the medullary portion of the rat thick ascending limb. Maximal adenylate cyclase stimulations achieved in that segment (31-fold) were higher than those obtained in collecting tubules from the same rats (22-fold). From comparisons of absolute maximal responses it can be calculated that thick ascending limbs account for about 80% of the response to vasopressin of a kidney medulla homogenate. The apparent Km value of adenylate cyclase activation (from 10(-9)-2 x 10(-8) M) in thick ascending limbs was higher in each experiment than that simultaneously measured in the collecting tubules from the same rats (2 x 10(-10)-3 x 10(-9) M). Such a lower sensitivity is probably not due to a greater hormone degradation by the thick ascending limb samples. Experiments using structural analogues of the oxytocin series ([deamino-6-carba]oxytocin and vasotocin) did not give evidence for different vasopressin receptors in the thick ascending limb and the collecting tubule. A step beyond the hormone-receptor interaction, thus, must account for the different patterns of adenylate cyclase response to vasopressin of these two segments.

Vasopressin-Dependent Adenylate Cyclase Activities in the Rat Kidney Medulla: Evidence for Two Separate Sites of Action*

Multiple hormonal control of adenylate cyclase in distal segments of the rat kidney.

The sensitivity to catecholamines of the adenylate cyclase (AC) activity contained in single tubule samples was investigated on 10 different well defined segments, isolated by microdissection from collagenase treated rabbit kidneys.

M. Imbert-Teboul

Papers

Distribution of hormone-dependent adenylate cyclase in the nephron and its physiological significance.

Vasopressin-Dependent Adenylate Cyclase Activities in the Rat Kidney Medulla: Evidence for Two Separate Sites of Action*

Multiple hormonal control of adenylate cyclase in distal segments of the rat kidney.

Catecholamine sensitive adenylate cyclase activity in different segments of the rabbit nephron

Inhibition of α2-adrenergic agonists on AVP-induced cAMP accumulation in isolated collecting tubule of the rat kidney☆