Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Results regarding the nitric oxide (NO) system in uraemia are contradictory. L-arginine, the precursor of NO, is also metabolized by arginase to form ornithine and urea. In the present study, endothelial NO production and arginine metabolism in uraemia were assessed. In addition an in vivo model was used to examine excess consumption of NO in uraemia. NO and amino acid measurements were made from basal and stimulated (by bradykinin) uraemic and control endothelial cells. Reverse-transcriptase PCR was used to assess endothelial NO synthase (eNOS) and inducible NOS (iNOS) expression. Finally, aortae of uraemic rats were stained for nitrotyrosine (a marker of peroxynitrite). Basal uraemic cells produced more NO than the control cells. L-arginine levels were greater in uraemic (supernatants/cells), but ornithine levels were higher in control (supernatants/cells). Following stimulation, NO levels in supernatants were similar, but the rise in NO production was greater in control compared with uraemic cells; l-arginine levels still remained higher in uraemic supernatants/cells. Differences in ornithine concentration (supernatants/cells) disappeared following bradykinin stimulation, due to a rise in ornithine levels in the uraemic group. There was no difference in eNOS expression, nor was iNOS detected in either group. Only aortae from uraemic rats showed evidence for nitrotyrosine staining. These studies demonstrated increased basal NO release in uraemic endothelial cells, perhaps by inhibition of arginase and hence diversion of arginine to the NO pathway. The increased NO produced under basal conditions may be inactive due to excessive consumption, resulting in peroxynitrite formation. Interestingly, bradykinin appears to restore arginase activity in uraemia, resulting in normalization of NO production.
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PMID:Altered L-arginine metabolism results in increased nitric oxide release from uraemic endothelial cells. 1209 1

Acute kidney injury (AKI) induces adaptive responses within proximal tubular (PT) cells that serve to protect them from further ischemic or toxic damage. However, it is not known whether uremia, a potential consequence of AKI, independently alters susceptibility to tubular injury. To address this issue, we subjected CD-1 mice to bilateral ureteral transection (BUTx), which produces uremia (blood urea nitrogen approximately 150 mg/dl) in the absence of direct renal damage. PT segments were then isolated from BUTx and control mice and subjected to in vitro hypoxic injury. Additionally, "in vitro uremia" was modeled in isolated tubules or in cultured PT (HK-2) cells by addition of 1) peritoneal dialysate (obtained from mice with bilateral ureteral obstruction), 2) peritoneal fluid (from BUTx mice), or 3) normal human urine (pH 7.4, with and without boiling). Effects on injury severity (lactate dehydrogenase release) were assessed. Finally, because uremia is a prooxidant state, it was hypothesized that BUTx would increase renal lipid peroxidation (malondialdehyde) and induce heme oxygenase-1 (HO-1), a redox-sensitive cytoprotective protein. BUTx conferred striking protection against hypoxic damage. This could be partially modeled in tubules and HK-2 cells by induction of in vitro uremia. Urine's protective action was heat labile (largely destroyed by boiling). BUTx caused a tripling of renal malondialdehyde and HO-1 protein levels. Increased HO-1 transcription was likely involved, as indicated by a tripling of HO-1 mRNA and RNA polymerase II binding along the HO-1 gene (chromatin immunoprecipitation assay). "Gene-activating" histone modifications [H3K4 trimethylation (H3K4m3) and histone 2 variant (H2A.Z)] at HO-1 gene loci were also observed. Uremia, per se, can contribute to the AKI-induced cytoresistance. Low-molecular-weight, heat-labile, cytoprotective factor(s) and uremia-induced renal stress responses (e.g., HO-1 gene activation) are likely involved. Finally, renal HO-1 induction following AKI may reflect direct cell injury effects and adaptations to uremia.
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PMID:Uremia induces proximal tubular cytoresistance and heme oxygenase-1 expression in the absence of acute kidney injury. 1903 45

Inflammatory cytokines are evoked by acute kidney injury (AKI) and may contribute to evolving renal disease. However, the impact of AKI-induced uremia on proinflammatory (e.g., TNF-alpha, MCP-1, TGF-beta1) and anti-inflammatory (e.g., IL-10) cytokine gene expression remains unknown. This study was undertaken to gain some initial insights into this issue. CD-1 mice were subjected to left renal ischemia-reperfusion (I/R) in the absence or presence of uremia (+/- right ureteral transection). TNF-alpha, MCP-1, TGF-beta1, and IL-10 mRNAs, cytokine protein levels, and RNA polymerase II (Pol II) recruitment to these genes were assessed. Renal cytokine mRNA levels were also contrasted with unilateral vs. bilateral renal parenchymal damage (I/R or ureteral obstruction). Potential effects of uremia on cytokine mRNAs in the absence of parenchymal renal damage [bilateral ureteral transection (BUTx)] were sought. Finally, the impact of simulated in vitro uremia (HK-2 tubular cells exposed to peritoneal dialysate from uremic vs. normal mice) on cytokine mRNA and microRNA profiles was assessed. Uremia blunted TNF-alpha, MCP-1, and TGF-beta1 mRNA increases in all three in vivo parenchymal acute renal failure models. These results were paralleled by reductions in cytokine protein levels and Pol II recruitment to their respective genes. Conversely, uremia increased IL-10 mRNA, both in the presence and absence (BUTx) of parenchymal renal damage. The uremic milieu also suppressed HK-2 cell proinflammatory cytokine mRNA levels and altered the expression of least 69 microRNAs (P < 0.0001). We conclude that both pro- and anti-inflammatory cytokine gene expressions are influenced by uremia, with a potential predilection toward an anti-inflammatory state. Changes in gene transcription (as reflected by Pol II recruitment), and possible posttranscriptional modifications (known to be induced by microRNAs), are likely involved.
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PMID:Uremia impacts renal inflammatory cytokine gene expression in the setting of experimental acute kidney injury. 1965 11