Chronic inhibition of nitric oxide production aggravates diabetic nephropathy in Otsuka Long-Evans Tokushima Fatty rats.

Nitric oxide (NO) is known to play a role in diabetic nephropathy, but the molecular basis for this effect remains unclear. Otsuka Long-Evans Tokushima Fatty spontaneous diabetic rat models were used along with Long-Evans Tokushima Otuska rat models as age-matched controls. Either L-arginine (a NO precursor) or L-NAME (a nitric oxide synthase inhibitor) was administered from the age of 22 weeks. Clinical parameters and serum and urinary NO2+NO3 levels were measured, in addition to renal histological findings and ED-1-positive cell counts in glomeruli. There were no significant differences in creatinine clearance between any of the groups at any point. The levels of urinary NO2+NO3 in the diabetic group were significantly lower than those in the control groups after 40 weeks; that in the L-NAME diabetic group was significantly lower than in the other diabetic groups at 52 weeks. Compared with the other diabetic groups, the L-NAME diabetic group had significantly higher urinary protein excretion levels, histological scores, and numbers of ED-1-positive cells in glomeruli. Diabetic rats administered L-arginine excreted more urinary protein than the diabetic controls. Diabetic nephropathy was exacerbated drastically by a nitric oxide synthase inhibitor and mildly by a NO precursor. These data suggested that NO may modify type 2 diabetic nephropathy in Otuska Long-Evans Tokushima Fatty rats through factors other than hemodynamics.