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Upregulation of renal inducible NO synthase and proximal tubule damage during human endotoxemia

In the kidney, the free radical nitric oxide (NO) participates in several vital processes, although excessive NO production, through inducible NO synthase (iNOS), can be cytotoxic. iNOS is predominantly, but only weakly, expressed in renal proximal tubules. Animal experiments demonstrate that an induction in iNOS expression occurs during systemic inflammation. In humans, renal effects of endotoxemia are unknown.

The objective of the present study was to investigate the pathophysiological role of iNOS induction in renal proximal tubules during experimental endotoxemia in humans.

A bolus injection of 2 ng/kg lipopolysaccharide of Escheria Coli (0113) was administered to eight healthy volunteers (four male/four female, age 24 ± 3 years), and 11 volunteers (five male/six female, age 22 ± 2 years) received the vehicle only (controls). At different time points, arterial blood in urine was collected and analyzed for nitrates/nitrites, the stable metabolites of NO. The amount of iNOS mRNA was determined by quantitative real-time RT-PCR from isolated cells of the urine. The urinary excretion of both glutathione-S-transferase-α (GST-α, present only in proximal tubular cells) and glutathione-S-transferase-π (GST-π, confined to distal tubular cells) were measured as well.

Administration of endotoxin resulted in the expected increase of proinflammatory cytokines (TNF-α from < 0.015 to 856 ± 158 pg/ml, P = 0.002), accompanied by fever (maximum temperature 38.7 ± 0.3°C, P < 0.0001), flu-like symptoms and cardiovascular changes (heart rate from 63 ± 3 bpm at baseline to 91 ± 3 bpm at t = 5 hours, P < 0.0001; and mean arterial pressure from 96 ± 3 mmHg to 79 ± 4 mmHg, P < 0.0001). All changes were significantly different from the control group. Blood samples did not show a significant change in NO metabolites following the administration of endotoxin. Twelve hours after endotoxin administration, the urinary level of NO metabolites doubled (P < 0.05), whereas no significant change was observed in the control group. This effect was associated with an increase in iNOS mRNA measured 24 hours after endotoxin administration. Urinary excretion of GST-α increased from 0.7 ± 0.3 μmol/hour to 3.1 ± 1.3 μmol/hour at t = 12 hours (P < 0.01), whereas GST-π remained unchanged (from 0.2 ± 0.04 to 0.4 ± 0.13 μmol/hour). In controls, no difference in both GST-α and GST-π excretion was observed.

Our results indicate that systemic inflammation induced by endotoxin in humans results in upregulation of renal iNOS, associated with proximal tubule injury.

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Heemskerk, S., Pickkers, P., van Eijk, L. et al. Upregulation of renal inducible NO synthase and proximal tubule damage during human endotoxemia. Crit Care 8 (Suppl 1), P197 (2004).

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