A variety of solid tumors secrete proteins that are immunochemically distinct from parathyroid hormone (PTH) but activate PTH-responsive adenylate cyclase. Such PTH-like proteins have been proposed as mediators of the hypercalcemia and hypophosphatemia frequently associated with malignancies. We purified to apparent homogeneity a PTH-like protein with a molecular weight of 6,000, that is produced by human renal carcinoma cells. The amino-terminal sequence of the PTH-like protein and that of human PTH were found to display at least five identities in the first 13 positions. The purified protein bound to PTH receptors, activated adenylate cyclase in renal plasma membranes, and stimulated cAMP formation in rat osteosarcoma cells. The PTH-like protein reproduced two additional effects of PTH, stimulation of bone resorption in fetal rat limb bone cultures and inhibition of phosphate uptake in cultured opossum kidney cells. These properties are consistent with a role for PTH-like proteins as mediators of the syndrome of malignancy-associated hypercalcemia.
This review discusses the activation of transport pathways during volume regulation, including their characteristics, the possible biochemical pathways that may mediate the activation of transport pathways, and the relations between volume regulation and transepithelial transport in renal cells. Many cells regulate their volume when exposed to an anisotonic medium. The changes in cell volume are caused by activation of ion transport pathways, plus the accompanying osmotically driven water movement such that cell volume returns toward normal levels. The swelling of hypertonically shrunken cells is termed regulatory volume increase (RVI) and involves an influx of NaCl into the cell via either activation of Na-Cl, Na-K-2Cl cotransport systems, or Na+-H+ and Cl(-)-HCO3- exchangers. The reshrinking of hypotonically swollen cells is termed regulatory volume decrease (RVD) and involves an efflux of KCl and water from the cell by activation of either separate K+ and Cl-conductances, a K-Cl cotransport system, or parallel K+-H+ and Cl(-)-HCO3- exchangers. The biochemical mechanisms involved in the activation of transport systems are largely unknown, however, the phosphoinositide pathway may be implicated in RVI; phorbol esters, cGMP, and Ca2+ affect the process of volume regulation. Renal tubular cells, as well as the blood cells that traverse the medulla, are subjected to increasing osmotic gradients from the corticomedullary junction to the papillary tip, as well as changing interstitial and tubule fluid osmolarity, depending on the diuretic state of the animal. Medullary cells from the loop of Henle and the papilla can volume regulate by activating Na-K-2Cl cotransport or Na+-H+ and Cl(-)-HCO3- exchange systems. Both Na-Cl and Na-K-2Cl cotransport systems have been identified in the medullary Loop of Henle and it is postulated that the Na-K-2Cl cotransport system predominates during RVI and affects transepithelial NaCl transport while the Na-Cl cotransport system may function during RVD in these cells.
The present studies examined the mechanism of bicarbonate transport across basolateral membrane vesicles prepared from rabbit renal cortex. Isotopic sodium uptake was stimulated by bicarbonate when compared with gluconate (2.5 nmol/mg protein per 5 s versus 1.4 nmol/mg protein per 5 s), and this process was inhibited by disulfonic stilbenes. Imposition of an interiorpositive potassium diffusion potential further stimulated isotopic sodium uptake to 3.4 nmol/mg protein per 5 s, an effect that occurred only in the presence of bicarbonate and was blocked by disulfonic stilbenes. Kinetic analysis of the rate of bicarbonatedependent sodium uptake as a function of sodium concentration revealed saturable stimulation with a V... of 2.7 nmol/mg protein per 2 s and a Km of 10.4 mM. The effect of bicarbonate concentration on bicarbonate-dependent sodium uptake was more complex. The present results demonstrate an electrogenic (negatively charged) sodium/bicarbonate cotransporter in basolateral membrane vesicles from the rabbit renal cortex. The electrogenicity implies a stoichiometry of at least two bicarbonate ions for each sodium ion.
A homogeneous population of single cells from the thick ascending limb of Henle's loop (TALH) has been isolated from the rabbit kidney medulla. A total medullary cell suspension was prepared by a series of collagenase, hyaluronidase, and trypsin digestions and separated on a Ficoll gradient (2 .6-30.7% wt/wt) . Morphologically, the cells isolated from the TALH were homogeneous and showed polarity within their plasma membrane structure, with a few blunt microvilli on their apical surface and deep infoldings of the basal-lateral membrane . Biochemically, the TALH cells were highly enriched in calcitonin-sensitive adenylate cyclase and Na, K-ATPase . Alkaline phosphatase and arginine vasopressin-sensitive adenylate cyclase, highly concentrated in proximal tubule and collecting duct, were present only in low concentrations in the TALH cells . Additionally, furosemide, a diuretic inhibiting sodium chloride transport in the TALH in vivo, inhibited oxygen consumption of the TALH cells in a closedependent manner . The TALH cells were viable, as judged by morphological appearance, trypan blue exclusion, the response of oxygen consumption to 2,4-dinitrophenol, succinate and ouabain, and the cellular Na, K and ATP levels .
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