Regulation of the renal Na+-H+ exchanger by protein phosphorylation.
ABSTRACT Starting from observations in intact cells and extending to studies in native membranes and solubilized membrane proteins, a significant body of evidence has been accumulated to indicate that some of the short-term regulatory influences on the Na+-H+ exchanger in the apical membrane of the proximal convoluted tubule act via protein phosphorylation mediated by specific protein kinases. Protein phosphorylation mediated by PKA inhibits the Na+-H+ exchanger while that mediated by PKC stimulates activity. The effect of PKA and PKC on the Na+-H+ exchanger in native membranes and in solubilized brush border membrane proteins appears to be consistent with most of the published observations in intact cells. Further studies using solubilized, renal brush border membrane proteins indicated that protein phosphorylation mediated by CaM-kinase II inhibited the activity of the Na+-H+ exchanger. The physiologic significance of this observation in intact cells remains to be determined. It is hoped that the types of experimental approaches outlined in this review will yield additional insights into the structure of the Na+-H+ exchanger and to a clearer understanding of its physiologic regulation.
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ABSTRACT: Calcitonin (CT), which regulates serum calcium through its actions in bone and the kidney tubule, also has a potent natriuretic effect in vivo. Na reabsorption in the proximal kidney tubule is mostly dependent on the activity of the Na,K-ATPase and the apical Na/H exchanger. We have previously shown that CT regulates the activity of the Na,K-ATPase in the proximal kidney tubule cell line LLC-PK_1 in a cell cycle-dependent manner. We report here that, in the same cells, CT also regulates the Na/H exchanger through a cell cycle-specific activation of the Ca/calmodulin-dependent protein kinase II. In G_2 phase, no changes in ethylisopropyl amiloride-sensitive 22Na uptake is observed, despite an increase in cAMP. In contrast, the hormone inhibits the apical exchanger when the cells are in S phase, resulting in an 80% inhibition of 22Na uptake. These results demonstrate that CT affects the activity of the two major proximal tubule Na transport systems and may help clarify the mechanisms by which CT regulates Na^+ reabsorption.Proceedings of the National Academy of Sciences 03/1994; 91(6):2115-2119. DOI:10.1073/pnas.91.6.2115 · 9.81 Impact Factor
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ABSTRACT: The objective of this study was to evaluate the effect of parathyroidectomy on the renal function in rats treated with saline (control), low-dose gentamicin (GM, 4 mg/kg per day), or high-dose GM (40 mg/kg per day) for 10 consecutive days. Gentamicin sulfate was dissolved in saline. A group of rats were subjected to thyroparathyroidectomy (PTX) 2 to 3 days before the beginning of the GM treatment. Thyroxine (1 μg/100 g body weight) was subcutaneously injected daily into PTX rats. In rats with saline infusion, a significant reduction in renal functional variables was obtained after PTX. When GM treatment and PTX were both present, a further impairment in the glomerular filtration rate and the urine/plasma inulin ratio was observed, suggesting additive effects. In rats infused with ammonium chloride to cause metabolic acidosis, a decline in glomerular filtration rate was obtained, a condition that was aggravated when GM treatment and PTX were both present. Acid excretion was significantly reduced in PTX groups, mainly during acidosis. In acidotic PTX rats treated with both low and high GM doses, the excreted amount of acid was strongly impaired, compared with the acidotic non-PTX GM group. These results show that in the PTX rats nephrotoxicity of GM is increased, which suggests that in this experimental model, parathyroid hormone may exert a protective effect during aminoglycoside treatment.Current Therapeutic Research 04/1997; 58(4):272-280. DOI:10.1016/S0011-393X(97)80023-9 · 0.45 Impact Factor
Pediatric Nephrology 04/1996; 10(2):236-244. DOI:10.1007/s004670050103 · 2.88 Impact Factor