Downregulation of neuronal nitric oxide synthase (nNOS) within the paraventricular nucleus in Ins2Akita-type-1 diabetic mice contributes to sympatho-excitation

• Published in: Nitric oxide Vol. 154; pp. 1 - 7
• Main Authors: Patel, Tapan A., Gao, Lie, Boomer, Shane H., Liu, Xuefei, Patel, Kaushik P., Zheng, Hong
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 01-02-2025
• Subjects: Angiotensin II; Neurogenic hypertension; nNOS; Paraventricular nucleus; Paraventricular nucleus; Neurogenic hypertension; Angiotensin II; nNOS
• ISSN: 1089-8603; 1089-8611; 1089-8611
• DOI: 10.1016/j.niox.2024.11.001

Activation of both renin-angiotensin system (RAS) and the sympathetic system is the primary etiologic event in developing cardiovascular complications in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Here we attempted to investigate diabetes-linked cardiovascular dysregulation due to angiotensin II (Ang II)-mediated reduction in neuronal nitric oxide (NO) synthase (nNOS) within the paraventricular neuleus (PVN). In the present study, we used Ins2+/−Akita (a spontaneous, insulin-dependent genetic diabetic non-obese murine model) and wild-type (WT) littermates mice as controls. At 14 weeks of age, we found the Akita mice had increased renal sympathetic nerve activity and elevated levels of plasma norepinephrine. There was decreased expression of nNOS protein (Akita 0.43 ± 0.11 vs. WT 0.75 ± 0.05, P < 0.05) in the PVN of Akita mice. Akita mice had increased expression of angiotensin-converting enzyme (ACE) (Akita 0.58 ± 0.05 vs. WT 0.34 ± 0.04, P < 0.05) and Ang II type 1 receptor (Akita 0.49 ± 0.03 vs. WT 0.29 ± 0.09, P < 0.05), decreased expressions of ACE2 (Akita 0.17 ± 0.05 vs. WT 0.27 ± 0.03, P < 0.05) and angiotensin (1–7) Mas receptor (Akita 0.46 ± 0.02 vs. WT 0.77 ± 0.07, P < 0.05). Futher, there were increased protein levels of protein inhibitor of nNOS (PIN) (Akita 1.75 ± 0.08 vs. WT 0.71 ± 0.09, P < 0.05) with concomitantly decreased catalytically active dimers of nNOS (Akita 0.11 ± 0.04 vs. WT 0.19 ± 0.02, P < 0.05) in the PVN in Akita mice. Our studies suggest that activation of the excitatory arm of RAS, leads to a decrease NO, causing an over-activation of the sympathetic drive in DM.
•Ins2+/-Akita had increased renal sympathetic nerve activity resulting in increased arterial pressure.•There was decreased nNOS and increased PIN of Akita mice resulting in decreased catalytically active dimers of nNOS.•Akita mice had increased expression of angiotensin-converting enzyme (ACE) and Ang II type 1 receptor.•Akita mice had decreased expressions of ACE2 and angiotensin (1-7) Mas receptor indicating an increased RAS activation.•The studies indicate a decrease NO system, resulting in over-activation of sympathetic drive in diabetes.