Effects of long-term inhibition of neuronal nitric oxide synthase (NOS1) in uninephrectomized diabetic rats.
Nitric oxide (NO) has been implicated in the pathogenesis of renal hemodynamic changes in diabetes mellitus (DM). However, the role of NO in the pathophysiology of diabetic nephropathy remains controversial. Renal hemodynamic changes in experimental DM can be acutely normalized by selective inhibition of neuronal NO synthase (nNOS). This observation suggests a nephroprotective potential of nNOS inhibition in DM. To explore this issue we assessed the long-term effects (12 weeks) of selective nNOS inhibition with the specific inhibitor S-methyl-L-thiocitrulline (SMTC) in uninephrectomized control and streptozotocin-diabetic rats. No beneficial effects of SMTC were observed in nondiabetic controls. In contrast, SMTC delayed the development of proteinuria (32+/-8 vs. 53+/-9 mg/24h, week 8, p < 0.05) and glomerulosclerosis (GS, 0.30+/-0.08 vs. 0.57+/-0.05, p < 0.05) in diabetic rats. These effects coincided with early effects of treatment on the glomerular filtration rate, and were associated with lower renal expression of nNOS. Furthermore, SMTC-treated diabetic rats demonstrated reduced weight gain and urinary sodium excretion as compared to vehicle-treated counterparts, despite similar metabolic control and blood pressure. In summary, long-term nNOS inhibition had modest nephroprotective effects in uninephrectomized diabetic rats. These effects may be mediated by renal hemodynamic mechanisms, as well as by lower food (protein) intake.
Komers
Radko
R
Division of Nephrology and Hypertension, Oregon Health and Science University, PP262, 3314 SW US Veterans Hospital Road, Portland, OR 97239-2940, USA.
Lindsley
Jessie N
JN
Oyama
Terry T
TT
Anderson
Sharon
S
D000818:Animals; D002956:Citrulline / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D051546:Cyclooxygenase 2; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007672:Kidney Cortex / Q000737:chemistry; D008297:Male; D009392:Nephrectomy; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000037:antagonists & inhibitors*; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D011451:Prostaglandin-Endoperoxide Synthases / Q000032:analysis; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011507:Proteinuria / Q000188:drug therapy / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D020011:Protective Agents; D002956:Citrulline; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D013890:Thiourea; C086717:S-methylthiocitrulline