Albuminuria and renal disease are considered integral components of metabolic syndrome, although the underlying pathogenic mechanisms are unclear. We tested the hypothesis that alterations of renal NO metabolism may play a role in renal manifestations of this syndrome by examining young ZSF rats (Charles River Labs) from 8 to 24 weeks (n = 6) for renal disease and renal NO metabolism. Body weights and arterial blood pressures (using tail cuff plethysmography) were recorded weekly. Serum was collected for glucose, lipid profile, creatinine, and NOx (nitrites and nitrates) measurements and 24-hour urine was collected in metabolic cages for measurement of creatinine, protein, 8-OHdG, an indicator of mitochondrial oxidative stress, and NOx (NO metabolites) at the beginning and the end of the study. The rats were euthanized at the end of study, kidneys harvested and sections examined for histopathology, and tissue homogenates examined for protein expression of NOS isoforms. By the 24th week, the rats displayed full-blown metabolic syndrome and overt proteinuria (534 6 54 mg/kg/d) with modest renal failure (1.67 6 0.2 at 24 wks vs 0.77 6 0.19 mg/dL at 8 wks, p < .05). Renal histology showed severe interstitial injury, tubular dilatation, arteriolar dilatation, and minimal glomerular changes with thickening of basement membrane. Renal expression of NOS isoforms, especially eNOS and iNOS, were decreased with decreased urinary excretion of NOx (5.6 6 1.1 μM/kg at 24 wks vs 12.3 μM/kg at 8 wks, p < .01). These changes were associated with increased urinary 8-OHdG (2,466 6 176 at 24 wks vs 815 6 143 ng/day/kg at 8 wks, p < .05). We conclude that metabolic syndrome is associated with structural and functional abnormalities of the kidney that may be related to decreased renal NO activity and enhanced oxidative stress.
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