Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes

Renal plasma flow (RPF) and glomerular filtration rate (GFR) are markedly increased during pregnancy. We recently reported that the renal hemodynamic changes observed during pregnancy in rats are associated with enhanced renal protein expression of neuronal nitric oxide synthase (nNOS). The purpose of this study was to determine the role of nNOS in mediating renal hemodynamic changes observed during pregnancy. To achieve this goal, we examined the effects of the nNOS inhibitor 7-nitroindazole (7-NI) on kidney function in normal conscious, chronically instrumented virgin ( n = 6) and pregnant rats ( n = 9) at day 16 of gestation. Infusion of 7-NI had no effect on RPF (4.7 ± 0.7 vs. 4.8 ± 0.9 ml/min), GFR (2.2 ± 0.2 vs. 2.5 ± 0.4 ml/min), or mean arterial pressure (MAP; 127 ± 7 vs. 129 ± 10 mmHg) in virgin rats. In contrast, 7-NI infused into pregnant rats decreased RPF (8.9 ± 1.6 vs. 6.5 ± 1.4 ml/min) and GFR (4.4 ± 0.7 vs. 3.3 ± 0.7 ml/min) while having no effect on MAP (123 ± 4 vs. 123 ± 3 mmHg). In summary, inhibition of nNOS in pregnant rats at midgestation results in significant decreases in RPF and GFR. nNOS inhibition in virgin rats had no effect on renal hemodynamics. These data suggest that nNOS may play a role in mediating the renal hemodynamic changes that occur during pregnancy.

Download Full-text

Role of neuronal nitric oxide synthase (NOS1) in the pathogenesis of renal hemodynamic changes in diabetes

AJP Renal Physiology ◽

10.1152/ajprenal.2000.279.3.f573 ◽

2000 ◽

Vol 279 (3) ◽

pp. F573-F583 ◽

Cited By ~ 62

Author(s):

Radko Komers ◽

Jessie N. Lindsley ◽

Terry T. Oyama ◽

Kristen M. Allison ◽

Sharon Anderson

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Renal Plasma Flow ◽

Diabetic Rats ◽

Hemodynamic Changes ◽

Renal Hemodynamic ◽

Streptozotocin Diabetic Rats ◽

Oxide Synthase ◽

Nos Isoforms

Nitric oxide (NO) has been implicated in the pathogenesis of renal hemodynamic changes in diabetes mellitus. However, the contribution of nitric oxide synthase (NOS) isoforms to intrarenal production of NO in diabetes remains unknown. To explore the role of NOS1 in the control of renal hemodynamics in diabetes, we assessed renal responses to inhibition of NOS1 with S-methyl-l-thiocitrulline (SMTC; administered into the abdominal aorta) in moderately hyperglycemic streptozotocin-diabetic rats (D) and their nondiabetic (C) and normoglycemic diabetic counterparts. The contribution of other NOS isoforms was also evaluated by assessing the responses to nonspecific NOS inhibition [ N G-nitro-l-arginine methyl ester (l-NAME)] in SMTC-treated diabetic rats. The number of NOS1-positive cells in macula densa of D and C kidneys was also evaluated by immunohistochemistry. D rats demonstrated elevated glomerular filtration rate (GFR) compared with C. SMTC (0.05 mg/kg) normalized GFR in D but had no effect in C. SMTC-induced reduction of renal plasma flow (RPF) was similar in C and D. Normoglycemic diabetic rats demonstrated blunted renal hemodynamic responses to NOS1 inhibition compared with hyperglycemic animals. Mean arterial pressure was stable in all groups. l-NAME induced a further decrease in RPF, but not in GFR, in D rats treated with SMTC. Immunohistochemistry revealed increased numbers of NOS1-positive cells in D. These observations suggest that NOS1-derived NO plays a major role in the pathogenesis of renal hemodynamic changes early in the course of diabetes. NOS1 appears to be the most important isoform in the generation of hemodynamically active NO in this condition.

Download Full-text