An analysis of renal nitric oxide contribution to hyperfiltration in diabetic rats

We have investigated whether nitric oxide (NO) generation is increased in d iabetes and whether specific NO synthase (NOS) isoforms are up-regulated in 4-week diabetic male Wistar rats. Glomerular filtration rate (GFR), kidney weight, and urinary nitrate (NOx) generation were measured in the followin g groups (n = 6): normal control animals, diabetic animals, diabetic animal s given L-NIL (a selective iNOS inhibitor)(D + L-NIL), diabetic animals giv en L-NAME (a nonselective NOS inhibitor)(D + L-NAME), and control animals g iven L-NAME (C + L-NAME). Diabetes increased GFR (0.78 +/- 0.05 mL/min/100 g body wt vs 1.49 +/- 0.07 mL/min/100 g body wt, P<.01). L-NIL did not affe ct hyperfiltration, while L-NAME decreased GFR to values that were lower th an those in normal control animals, a response identical to that in non-dia betic control rats. L-NIL did not affect urinary NOx values, but L-NAME com pletely abolished the increase in urinary nitrates. Kidney weight was not a ffected by L-NIL, but L-NAME significantly attenuated kidney growth. Induci ble NOS (iNOS) and endothelial NOS (eNOS) mRNA levels measured by reverse t ranscription-polymerase chain reaction in diabetic rats were not changed as compared with levels in controls. Cyclic guanosine monophosphate responses to carbachol (an index of eNOS activity) in glomeruli from diabetic rats w ere significantly reduced as compared with those in controls, and guanylate cyclase responses to sodium nitroprusside were significantly decreased. Th erefore, renal NO generation, at least via eNOS and iNOS, is not the primar y cause of glomerular hyperfiltration in diabetes.