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

Abstract

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.

Effect of the antihepcidin Spiegelmer lexaptepid on inflammation-induced decrease in serum iron in humans

“…Currently, a phase 2 trial (clinicaltrials.gov #NCT01691040) investigates whether lexaptepid is able to elevate hemoglobin in cancer patients, and initial results from a pilot phase are encouraging. 19 Although an increase over time was noted for both total ironbinding capacity and plasma ferritin concentration after endotoxin administration, no differences between groups were observed (supplemental Figure 2A,B). No effect of lexaptepid was observed on innate immunity.…”

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

“…The effect of NO on renal function was investigated further in healthy human volunteers during endotoxemia (82). iNOS gene expression was highly induced after endotoxin administration accompanied by a marked increase in urinary NO metabolites excretion, which correlated strongly with the excretion of GST A1-1, a renal tubule injury marker.…”

Alkaline Phosphatase as a Treatment of Sepsis-Associated Acute Kidney Injury

“…Subsequent production of NO metabolites was attenuated and correlated with reduced urinary excretion of the proximal tubule injury marker, glutathione S-transferase A1-1 (Heemskerk et al, 2009). Inducible nitric-oxide synthase is constitutively expressed in the renal proximal tubule and during systemic inflammation its expression is rapidly increased, resulting in excess NO and successive production of harmful peroxynitrite, causing tubular damage (Heemskerk et al, 2006;Fortin et al, 2010).…”