PubMed · 14945694
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A BELLAVIA. 1952. [Hyperazotemic postoperative variations].. https://pubmed.ncbi.nlm.nih.gov/14945694/
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Sites of inflammation are characterized by significant changes in metabolic activity. Shifts in energy supply and demand can result in diminished delivery and/or availability of oxygen, leading to inflammation-associated tissue hypoxia and metabolic acidosis. These shifts in tissue metabolism, as indicated by previous studies, are frequently associated with vasculitis and profound recruitment of inflammatory cell types, particularly myeloid cells such as neutrophils (PMN) and monocytes. Here, we review recent work addressing the influence of hypoxia on development of inflammatory lesions, with particular emphasis on molecular pathways regulated by hypoxia-inducible factor (HIF).
BACKGROUND: In acute renal failure, a pronounced net protein catabolism occurs that has long been associated with corticoid action. By competitively blocking the glucocorticoid receptor with the potent antiglucocorticoid RU 38486, the present study addressed the question to what extent does corticoid action specific to uremia cause the observed muscle degradation, and does inhibition of glucocorticoid action reduce the protein wasting? METHODS: RU 38486 was administered in a dose of 50 mg/kg/24 h for 48 h after operation to fasted bilaterally nephrectomized (BNX) male adult Wistar rats and sham operated (SHAM) controls. Protein turnover was evaluated by high performance liquid chromatography (HPLC) of amino acid efflux in sera from isolated perfused hindquarters of animals treated with RU 38486 versus untreated controls. RESULTS: Administration of RU 38486 reduces the total amino acid efflux (TAAE) by 18.6% in SHAM and 15.6% in BNX and efflux of the indicator of net protein turnover, phenylalanine (Phe) by 33.3% in SHAM and 13% in BNX animals as compared to the equally operated, but untreated animals. However, the significantly higher protein degradation observed in BNX (0.6 +/- 0.2 nmol/min/g muscle) versus SHAM (0.2 +/- 0.1 nmol/min/g muscle) rats, as demonstrated by the marker of myofribrillar proteolytic rate, 3-Methylhistidine (3 MH) remains unaffected by administration of RU 38486 (0.5 +/- 0.1 v. 0.2 +/- 0.1 nmol/min/g muscle in BNX v. SHAM). CONCLUSION: RU 38486 does not act on changes of muscular protein turnover specific to uremia but reduces the effect of stress-stimulated elevated corticosterone secretion arising from surgery and fasting. A potentially beneficial effect against stress- induced catabolism in severe illness can be postulated that merits further study.
During chronic metabolic acidosis (CMA), the plasma levels of glutamine are increased and so is glutamine metabolism in the kidney tubule cells. Degradation of glutamine results in the formation of ammonium (NH(4)(+)) and bicarbonate (HCO(3)(-)) ions, which are excreted in the pre-urine and transported to the peritubular blood, respectively. This process contributes to counteract acidosis and to restore normal pH, but the molecular mechanism, the localization of the proteins involved and the regulation of glutamine transport into the renal tubular cells, remains unknown. SN1, a Na(+)- and H(+)-dependent glutamine transporter has previously been identified molecularly, and its mRNA has been detected in tubule cells in the medulla of the kidney. Now shown is the selective targeting of the protein to the basolateral membranes of the renal tubule cells of the S3 segment throughout development of the normal rat kidney. During CMA, SN1 expression increases five- to six-fold and appears also in cortical tubule cells in parallel with the increased expression and activity of phosphate-activated glutaminase, a mitochondrial enzyme involved in ammoniagenesis. However, SN1 remains sorted to the basolateral membranes. The unique ability of SN1 to change transport direction according to physiologic changes in transmembrane gradients of [glutamine] and pH and its sorting to the basolateral membranes and the presence of a putative pH responsive element in the 3' untranslated region (UTR) of the gene (supported here by the demonstration in CMA kidney of a protein that binds SN1 mRNA) are conducive to the function of this transporter in pH regulation.