Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effects of the (Sp) and (Rp) diastereomers of the phosphorothioate analogue of cyclic AMP (cAMPS) on the excretion of electrolytes in the isolated perfused rat kidney. cAMPS is highly permeant across the peritubular cell membrane and is not metabolized by the rat kidney (Coulson et al., Life Sci. 32: 1489-1498, 1983). Addition of 10 microM cAMPS(Sp) to the perfusate resulted in a significant phosphaturia, bicarbonaturia, magnesuria and natriuresis and no change in renal vascular resistance or glomerular filtration rate. Fractional excretion of calcium was elevated by cAMPS(Sp) but proportionately less than the fractional excretion of sodium so that the ratio of calcium to sodium clearances was significantly lowered. cAMPS(Rp) 10 or 100 microM was without effect on renal electrolyte excretion. The parathyroid hormone-like effects of the (Sp) diastereomer are consistent with its known ability to activate protein kinase.
 ...
PMID:Effects of (Sp)- and (Rp)-adenosine cyclic 3',5'-phosphorothioates on electrolyte excretion by the isolated perfused rat kidney. 298 44

It is known that parathyroidectomy, administration of parathyroid hormone (PTH), and dietary phosphate depletion or excess result in variations in phosphaturia and in phosphate transport through brush border membrane vesicles isolated from the kidneys of various animals. Parathyroid hormone has been shown to ultimately phosphorylate some brush border membrane proteins and it has been postulated that the resulting phosphaturia is related to this phosphorylation. However, it is not known whether the regulation of phosphate transport by the diet is affected through similar pathways. Our experiments were designed to study the phosphorylation of brush border membrane with [gamma-32P]ATP using the intrinsic protein kinase of the membranes. Five groups of rats were used: normal, phosphate loaded, phosphate depleted, and thyroparathyroidectomized and acutely loaded with parathyroid hormone. In each series of animals, the proteins whose phosphorylation was cAMP dependent were detected by sodium dodecyl sulfate polyacrylamide gel electrophoresis, and their phosphorylation with various concentrations of ATP, in the presence or absence of cAMP in the incubation medium, was quantified. In the normal rat, 17 proteins were phosphorylated, the phosphorylation of two of them (Mr, 71 000 and 84 000) being cAMP dependent. Maximal response to cAMP for these two proteins was obtained with 10 microM cAMP. The peaks of phosphorylation were observed at pH 7 for protein 71 000 and pH 10 for protein 84 000. When brush border membranes from normal rats were incubated with 10-100 microM ATP, cAMP-dependent phosphorylation increased to reach a maximal phosphorylation of 4.44 +/- 0.90 pmol/mg protein for protein 71 000 and 1.32 +/- 0.15 pmol/mg protein for protein 84 000.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Renal brush border membrane phosphorylation: influence of pH, cAMP and ATP concentrations, parathyroid hormone status, and dietary phosphate. 300 May 57

It is known that the administration of parathyroid hormone to dogs results in phosphaturia and decreased phosphate transport in brush-border vesicles isolated from the kidneys of those dogs. Parathyroid hormone has been shown to activate adenylate cyclase at the basal-lateral membrane of the renal proximal tubular cell. It has been postulated that parathyroid hormone-induced phosphaturia is effected through phosphorylation of brush-border protein by membrane-bound cAMP-dependent protein kinase. An experimental system was designed such that phosphorylation of brush-border vesicles and Na+-stimulated solute transport could be studied in the same preparations. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of membrane vesicles revealed cAMP-dependent phosphorylation of 2 protein bands (Mr = 96,000 and 62,000), which was enhanced by exposure of the inside of the membrane vesicles to ATP and cAMP. Cyclic AMP-dependent phosphorylation of brush-border vesicles was accompanied by inhibition of Na+-stimulated Pi but not D-glucose transport or 22Na+ uptake. When renal brush-border vesicles from parathyroidectomized and normal dogs were phosphorylated in vitro in the presence and absence of cAMP, both the cAMP-dependent phosphorylation and inhibition of Na+-stimulated Pi transport were greater in vesicles isolated from kidneys of parathyroidectomized dogs relative to control animals. We conclude that the cAMP-dependent phosphorylation of brush-border membrane-vesicle proteins is associated with specific inhibition of Na+-stimulated Pi transport. The phosphaturic action of parathyroid hormone (PTH) could be mediated through the cAMP-dependent phosphorylation of specific brush-border membrane proteins.
 ...
PMID:Cyclic AMP-dependent protein phosphorylation in canine renal brush-border membrane vesicles is associated with decreased phosphate transport. 627 74

PTH-induced phosphaturia is exerted in part by cAMP added to the renal tubular lumen under the influence of the hormone. Modulation of renal phosphate transport by luminal cAMP requires degradation of the nucleotide into adenosine by brush-border membrane ectoenzymes, among them ecto-5'-nucleotidase (5'-NU). Hormonal modulation of 5'-NU activity was evaluated in cultured opossum kidney cells. PTH (1-100 nM) stimulated 5'-NU in a time-, concentration-, and protein synthesis-dependent manner. The effect of PTH-(1-34) was mimicked by PTH-(3-34), which does not activates adenylate cyclase, and by phorbol 12-myristate 13-acetate (PMA), but not by forskolin or (Bu)2cAMP. Down-regulation or pharmacological inhibition of protein kinase-C (PKC) abolished the effect of PTH fragments and PMA. PTH fragments increased intracellular Ca2+ and translocated PKC activity to the membrane. PTH or PMA did not affect 5'-NU messenger RNA content. Inhibition of sodium-phosphate cotransport by extracellular cAMP was decreased by 5'-NU inhibition and was magnified by PTH. These results indicate that 1) PTH stimulates 5'-NU activity in renal proximal tubular cells in a manner involving PKC activation and de novo protein synthesis; and 2) this effect participates in PTH modulation of renal phosphate transport.
 ...
PMID:Parathyroid hormone stimulates ecto-5'-nucleotidase activity in renal epithelial cells: role of protein kinase-C. 786 81

The Na(+)/phosphate cotransporter NaPi-IIa (SLC34A1) is the major transporter mediating the reabsorption of P(i) in the proximal tubule. Expression and activity of NaPi-IIa is regulated by several factors, including parathyroid hormone, dopamine, metabolic acidosis, and dietary P(i) intake. Dopamine induces natriuresis and phosphaturia in vivo, and its actions on several Na(+)-transporting systems such as NHE3 and Na(+)-K(+)-ATPase have been investigated in detail. Using freshly isolated mouse kidney slices, perfused proximal tubules, and cultured renal epithelial cells, we examined the acute effects of dopamine on NaPi-IIa expression and localization. Incubation of isolated kidney slices with the selective D(1)-like receptor agonists fenoldopam (10 microM) and SKF-38393 (10 microM) for 1 h induced NaPi-IIa internalization and reduced expression of NaPi-IIa in the brush border membrane (BBM). The D(2)-like selective agonist quinpirole (1 microM) had no effect. The D(1) and D(2) agonists did not affect the renal Na(+)/sulfate cotransporter NaSi in the BBM of the proximal tubule. Studies with isolated perfused proximal tubules demonstrated that activation of luminal, but not basolateral, D(1)-like receptors caused NaPi-IIa internalization. In kidney slices, inhibition of PKC (1 microM chelerythrine) or ERK1/2 (20 microM PD-098089) pathways did not prevent the fenoldopam-induced internalization. Inhibition with the PKA blocker H-89 (10 microM) abolished the effect of fenoldopam. Immunoblot demonstrated a reduction of NaPi-IIa protein in BBMs from kidney slices treated with fenoldopam. Incubation of opossum kidney cells transfected with NaPi-IIa-green fluorescent protein chimera shifted fluorescence from the apical membrane to an intracellular pool. In summary, dopamine induces internalization of NaPi-IIa by activation of luminal D(1)-like receptors, an effect that is mediated by PKA.
 ...
PMID:Activation of dopamine D1-like receptors induces acute internalization of the renal Na+/phosphate cotransporter NaPi-IIa in mouse kidney and OK cells. 1554 13

Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) target the kidney to cause a phosphaturia. FGF23 also acts on the parathyroid to decrease PTH expression, but in chronic kidney disease (CKD) there are high-serum PTH and FGF23 levels and resistance of the parathyroid to FGF23. We now report that PTH acts on bone to increase FGF23 expression and characterize the signal transduction pathway whereby PTH increases FGF23 expression. Remarkably, we show that PTH is necessary for the high-FGF23 levels of early kidney failure due to an adenine high-phosphorus diet. Parathyroidectomy before the diet totally prevented the fivefold increase in FGF23 levels in kidney failure rats. Moreover, parathyroidectomy of early kidney failure rats corrected their high-FGF23 levels. Therefore, in early kidney failure, the high-FGF23 levels are dependent on the high-PTH levels. PTH infusion for 3 days to mice with normal renal function increased serum FGF23 and calvaria FGF23 mRNA levels. To demonstrate a direct effect of PTH on FGF23, we added PTH to rat osteoblast-like UMR106 cells. PTH increased FGF23 mRNA levels (4-fold) and this effect was mimicked by a PKA activator, forskolin. PTH also decreased SOST mRNA levels (3-fold). SOST codes for sclerostin, a Wnt pathway inhibitor, which is a PTH receptor (PTH1R) target. The effect of PTH was prevented by added sclerostin. Therefore, PTH increases FGF23 expression which involves the PKA and Wnt pathways. The effect of PTH on FGF23 completes a bone-parathyroid endocrine feedback loop. Importantly, secondary hyperparathyroidism is essential for the high-FGF23 levels in early CKD.
 ...
PMID:PTH increases FGF23 gene expression and mediates the high-FGF23 levels of experimental kidney failure: a bone parathyroid feedback loop. 2068 23