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Upregulation of Renal Inducible Nitric Oxide Synthase during Human Endotoxemia and Sepsis Is Associated with Proximal Tubule Injury

Suzanne Heemskerk^*, Peter Pickkers^*,, Martijn P.W.J.M. Bouw, Annelies Draisma, Johannes G. van der Hoeven, Wilbert H.M. Peters, Paul Smits^*, Frans G.M. Russel^*, and Rosalinde Masereeuw^*

^* Department of Pharmacology and Toxicology, Nijmegen Centre for Molecular Life Sciences, and Departments of Intensive Care Medicine and Gastroenterology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

Address correspondence to: Dr. Rosalinde Masereeuw, Department of Pharmacology and Toxicology (149), Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. Phone: +31-24-3613730; Fax: +31-24-3614214; E-mail: r.masereeuw{at}ncmls.ru.nl

The incidence and the mortality of septic acute kidney injury are high, partly because the pathogenesis of sepsis-induced renal dysfunction is not clear. The objective of this study was to investigate the upregulation of renal inducible nitric oxide synthase (iNOS) in human endotoxemia and sepsis and the effect of NO on tubular integrity. Septic patients and endotoxemia that was induced by a bolus injection of 2 ng/kg Escherichia coli LPS in human volunteers were studied. In addition, the effect of co-administration of the selective iNOS inhibitor aminoguanidine was evaluated. The urinary excretion of the cytosolic glutathione-S-transferase-A1 (GSTA1-1) and GSTP1-1, markers for proximal and distal tubule damage, respectively, was determined. In septic patients, an almost 40-fold induction of iNOS mRNA in cells that were isolated from urine was found accompanied by a significant increase in NO metabolites in blood. The mRNA expression of iNOS was induced 34-fold after endotoxin administration. LPS-treated healthy volunteers showed a higher urinary excretion of NO metabolites compared with control subjects. Urinary NO metabolite excretion correlated with urinary GSTA1-1 excretion, indicating proximal tubule damage, whereas no distal tubular damage was observed. Co-administration of aminoguanidine reduced the upregulation of iNOS mRNA, urinary NO metabolite, and GSTA1-1 excretion, indicating that upregulation of iNOS and subsequent NO production may be responsible for renal proximal tubule damage observed.

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