The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock

Albuszies, Gerd; Vogt, J.; Wachter, Ulrich; Thiemermann, Christoph; Leverve, Xavier; Weber, Sandra; Georgieff, Michael; Radermacher, Peter; Barth, Eberhard

doi:10.1007/s00134-007-0638-7

Cited by 22 publications

(16 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Effect of HCD with and without exposure to LPS on hepatic glucose metabolism It has been suggested that NO-biosynthesis may contribute to the development of hepatic dysfunction during sepsis by inhibiting the capacity of the liver to generate glucose (2,35). Accordingly, the association between the above results and alterations in hepatic gluconeogenesis was evaluated.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies revealed contradictory results suggesting a protective or detrimental role for iNOS under these circumstances (8,13). Concerning glucose metabolism, iNOS may profoundly and diversely modulate glucose production and/or utilization; thus, promoting hyperglycemia or hypoglycemia (2,22,33). iNOS can participate in glucose metabolism by stabilizing, and thus, activating, the transcription factor (TF) hypoxiainducible factor-1 (HIF1) (26).…”

mentioning

confidence: 99%

“…Currently, the role of iNOS in LPS-associated depression of gluconeogenesis is still controversial (2,35). However, in some of these studies conclusions were based upon the evaluation of PEPCK mRNA levels or its activity in vitro.…”

mentioning

confidence: 99%

See 2 more Smart Citations

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

Anavi

Hahn-Obercyger

Margalit

et al. 2013

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Aims: The current study aim was to elucidate the antihypoglycemic role and mechanism of inducible nitric oxide synthase (iNOS) under inflammatory stress. Methods: Liver inflammatory stress was induced in wild-type (WT) and iNOS-knockout (iNOS -/ -) mice by lipopolysaccharide (LPS) (5 mg/kg) with and without the background of nonalcoholic steatohepatitis (NASH)-Induced by high cholesterol diet (HCD, 6 weeks). Results: HCD led to steatohepatitis in WT and iNOS -/ -mice. LPS administration caused marked liver inflammatory damage only in cholesterol-fed mice, which was further exacerbated in the absence of iNOS. Glucose homeostasis was significantly impaired and included fatal hypoglycemia and inhibition of glycogen decomposition. In iNOS -/ -hypoxia-inducible factor-1 (HIF1), signaling was impaired compared to control WT. Using hydrodynamic gene transfer method HIF1a was expressed in the livers of iNOS -/ -mice, and significantly ameliorated cholesterol and LPS-induced liver damage. WT mice overexpressing HIF1a exhibited higher blood glucose levels and lower glycogen contents after LPS injection. Conversely, induction of HIF1a was not effective in preventing LPSinduced glucose lowering effect in iNOS -/ -mice. The critical role of NO signaling in hepatocytes glucose output mediated by HIF1 pathway was also confirmed in vitro. Results also demonstrated increased oxidative stress and reduced heme oxygenase-1 mRNA in the livers of iNOS -/ -mice. Furthermore, the amounts of plasma tumor necrosis factor-a (TNFa) and intrahepatic TNFa mRNA were significantly elevated in the absence of iNOS. Innovation and Conclusion: These data highlight the essential role of iNOS in the glycemic response to LPS in NASH conditions and argues for the beneficial effects of iNOS.

show abstract

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

Anavi

Hahn-Obercyger

Margalit

et al. 2013

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

show abstract

“…For example, increased renal oxygenation of lactate or gluconeogenesis could also explain lower pyruvate and lactate concentrations [52–54]. Alternatively, increased pyruvate dehydrogenase (PDH) activity may have contributed to lower lactate and pyruvate levels during early sepsis [55–57].…”

Section: Discussionmentioning

confidence: 99%

The effects of acute renal denervation on kidney perfusion and metabolism in experimental septic shock

Post

Taccone

et al. 2017

BMC Nephrol

View full text Add to dashboard Cite

BackgroundPerfusion deficits likely play an important role in the development of renal dysfunction in sepsis. Renal denervation may improve kidney perfusion and metabolism.MethodsWe randomized 14 female sheep to undergo bilateral surgical renal denervation (n = 7) or sham procedure (n = 7) prior to induction of sepsis. Renal blood flow (RBF) was measured with a pre-calibrated flowprobe. Laser Doppler probes were implanted to measure cortical and medullary perfusion. Cortical glucose, lactate and pyruvate levels were measured using the microdialysis technique. Creatinine clearance was determined. Sepsis was induced by peritonitis and fluid resuscitation was provided to avoid hypovolemia.ResultsRBF and cortical perfusion were higher in the denervated group during the first 6 h after induction of sepsis (P < 0.001 and P < 0.05, respectively), while medullary perfusion decreased similarly in both groups. After hypotension developed, RBF decreased to similar levels in both groups. Cortical pyruvate and lactate levels were lower in the denervated animals (P < 0.001 and P < 0.001, respectively). There were no differences between groups in creatinine clearance, urine output or time to oliguria.ConclusionDenervation thus caused an early increase in RBF that was distributed towards the kidney cortex. Although associated with an attenuation of early cortical metabolic alterations, denervation failed to prevent the deterioration in renal function.

show abstract

“…Most studies of the role of nitric oxide synthases (NOS) in sepsis have focused on inducible NOS (NOS2) and have shown that its expression and, in turn, overproduction of NO are pivotal in sepsis-induced hemodynamic changes and end-organ damage [1][2][3][4][5][6]. With regards to the constitutive isoforms of NOS, there is experimental evidence that endothelial NOS (NOS3) has an important role in sepsis as well.…”

Section: Introductionmentioning

confidence: 99%

Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis

et al. 2007

View full text Add to dashboard Cite

Objective-To investigate the role of neuronal nitric oxide synthase (NOS1) in murine polymicrobial peritonitis and sepsis. Design-Randomized experimental trial.Setting-Animal research facility. NIH-PA Author Manuscript NIH-PA Author Manuscript Subjects-B6129S NIH-PA Author ManuscriptInterventions-NOS1 +/+ and NOS1 -/-animals underwent cecal ligation and puncture (CLP) or sham surgery and received the NOS1 inhibitor 7-nitroindazole (7-NI) or vehicle.Measurements and main results-After CLP, genetic deficiency and pharmacologic inhibition of NOS1 significantly increased risk of mortality [8.69 (3.27, 23.1), p < 0.0001 and 1.71 (1.00, 2.92) p = 0.05, hazard ratio of death (95% confidence interval) for NOS1 -/-and 7-NItreated NOS1 +/+ respectively] compared with NOS1 +/+ animals. In 7-NI-treated NOS1 +/+ animals, there were increases (6 h) and then decreases (24 h), whereas in NOS -/-animals persistent increases in blood bacteria counts (p = 0.04 for differing effects of 7-NI and NOS1 -/-) were seen compared with NOS1 +/+ animals. After CLP, NOS1 -/-had upregulation of inducible NOS and proinflammatory cytokines and greater increases in serum tumor necrosis factor-α and interleukin-6 levels compared with NOS1 +/+ mice (all p < 0.05). Following CLP, there were similar significant decreases in circulating leukocytes and lung lavage cells (p ≤ 0.0008) and significant increases in peritoneal lavage cells (p = 0.0045) in all groups. Over 6 h and 24 h following CLP, compared with NOS1 +/+ , NOS -/-mice had significantly higher peritoneal cell concentrations {respectively 0.40 ± 0.09 vs 0.79 ± 0.15 [log(× 10 4 cells/ml)] averaged over both times p = 0.038}.Conclusions-Deficiency and inhibition of NOS1 increases mortality, possibly by increasing proinflamma-tory cytokine response and impairing bacterial clearance after CLP. These data suggest that NOS1 is important for survival, bacterial clearance, and regulation of cytokine response during infection and sepsis.

show abstract

The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock

Cited by 22 publications

References 62 publications

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

A Novel Antihypoglycemic Role of Inducible Nitric Oxide Synthase in Liver Inflammatory Response Induced by Dietary Cholesterol and Endotoxemia

The effects of acute renal denervation on kidney perfusion and metabolism in experimental septic shock

Neuronal nitric oxide synthase deficiency decreases survival in bacterial peritonitis and sepsis

Contact Info

Product

Resources

About