Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The lower O2 tension and more active anerobic metabolism that pertain in the inner medulla (IM) of kidney relative to cortex (C) are well recognized, but there is no evidence that O2 availability constitutes a limiting or regulatory factor in IM metabolism or function. In the present in vitro study, we examined the effects of O2 on adenosine 3',5'-monophosphate (cAMP) metabolism in slices of rat renal C and IM. After a 20-min incubation of slices in Krebs Ringer bicarbonate buffer with 95% O2 + 5% CO2 serving as the gas phase, the cAMP content of IM was 6-10 fold higher than that of C in either the presence or absence of 2 mM 1-methyl-3-isobutylxanthine in the incubation media. In slices of IM incubated for 20 min with 1-methyl-3-isobutylxanthine, cAMP was 22.5+/-SE 2.48 pmol/mg wet weight at 95% O2 and 4.37 without O2. Oxygenation of O2-deprived IM increased cAMP twofold in 2 min, an effect fully expressed in 5 min (fivefold increase). Further, cAMP of IM rose progressively and significantly over a range of atmospheric O2 content from 0 to 50% conditions which should reproduce and encompass O2 tensions that pertain in tissues in vivo. By contrast, basal cAMP content of C varied less than twofold in the presence of 95% versus no O2, implying that O2 modulation of cAMP was specific for IM. Indomethacin and meclofenamate, structurally distinct inhibitors of prostaglandin synthesis, both significantly decreased basal cAMP accumulation in oxygenated slices of IM but not of C. Meclofenamate also reduced basal adenylate cyclase activity determined in homogenates prepared from slices of IM which had been incubated at 95% O2. In slices of IM previously exposed to indomethacin or meclofenamate at 95% O2, a maximally effective concentration of exogenous prostaglandin E1 restored cAMP and adenylate cyclase activity to levels which approximated those observed at 95% O2 in the absence of an inhibitor of prostaglandin synthesis. These results suggest that O2 enhancement of cAMP content in IM may be mediated at least in part by local prostaglandins.
 ...
PMID:Modulation of the cyclic AMP content of rat renal inner medulla by oxygen: possible role of local prostaglandins. 18 90

A model has been presented for the role of the kidney in the physiologic and pathophysiologic control of erythropoiesis. It is postulated that an oxygen deficit created by anemia or hypobaric hypoxia results in the release of prostacyclin and its metabolite 6-keto PGE1, and the release of PGE2 with ischemic hypoxia. Prostacyclin, 6-keto-PGE1, or PGE2 activation of adenylate cyclase, an increase in cyclic AMP, activation of a protein kinase and the phosphorylation of hydrolases, which have been released from lysosomes by hypoxia, lead to increased biosynthesis of erythropoietin (Ep). The mechanism of labilization of lysosomes and the release of hydrolases from these cell organelles is postulated to be related to increases in cyclic GMP levels in a renal cell. An Ep-producing human renal carcinoma cell line grown in tissue culture has been demonstrated to produce significant amounts of PGE2. Meclofenamate, an inhibitor of prostaglandins synthesis, was found to inhibit in vitro production of PGE2, Ep, and dome formation in these renal carcinoma cells, giving support to our hypothesis that pathophysiologic production of Ep tumor cells depends upon prostaglandins production. An Ep-producing clone from this renal carcinoma cell line has been developed that contains low electron density (LED) cells after the cells reach confluency, which show a cytoplasm, with abundant and widely dilated endoplasmic reticulum, an oval nucleus, dispersed chromatin, and prominent nucleoli. These are the cells responsible for dome formation and Ep production. Non-EP-producing clones have also been produced from this renal carcinoma cell line, which did not produce domes even at high cell density and had a distinctly different cell type than the Ep-producing clone. Thus, it is postulated that prostacyclin (PGI2) and its metabolite 6-keto PGE1 play a significant role in hypoxic hypoxia stimulation of Ep production and PGE2 is involved in ischemic hypoxia and renal carcinoma cell production of Ep. A modulating effect of PGE2 and PGD2, the two primary bone marrow prostaglandins, has been proposed in Ep stimulation of the erythroid progenitor cell compartment (CFU-E and BFU-E).
 ...
PMID:Effects of prostaglandins on erythropoiesis. 654 52