TY - JOUR
T1 - Effects of long-term inhibition of neuronal nitric oxide synthase (NOS1) in uninephrectomized diabetic rats
AU - Komers, Radko
AU - Lindsley, Jessie N.
AU - Oyama, Terry T.
AU - Anderson, Sharon
N1 - Funding Information:
These studies were supported, in part, by grants from the American Diabetes Association, the Juvenile Diabetes Research Foundation, and the NIH (DK 63231).
PY - 2004/9
Y1 - 2004/9
N2 - 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/24 h, 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.
AB - 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/24 h, 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.
KW - Diabetic nephropathy
KW - Glomerular filtration rate
KW - Glomerulosclerosis
KW - NOS1
KW - Neuronal nitric oxide synthase
KW - Proteinuria
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U2 - 10.1016/j.niox.2004.08.005
DO - 10.1016/j.niox.2004.08.005
M3 - Article
C2 - 15491847
AN - SCOPUS:5644300736
SN - 1089-8603
VL - 11
SP - 147
EP - 155
JO - Nitric Oxide - Biology and Chemistry
JF - Nitric Oxide - Biology and Chemistry
IS - 2
ER -