Activation of both renin-angiotensin- system (RAS) and sympathetic system are the primary etiologic events in the development of hypertension in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Our previous studies have demonstrated that neuronal nitric oxide (nNOS) expression and nitric oxide (NO) mediated inhibition of sympathetic nerve activity (SNA) is markedly reduced in the paraventricular nucleus (PVN) of streptozotocin-induced diabetic rats. We have further demonstrated that Angiotensin II (Ang II) via Ang II type 1 receptors (AT
1
R) modulates the expression of nNOS in the PVN, which augments sympathetic outflow. Here we hypothesized that DM-linked hypertension and cardiovascular dysregulation is due to the reduction in nNOS with the PVN. To test the hypothesis, we used Ins2
+/-
Akita (a spontaneous, insulin dependent genetic diabetic murine model) which showed an increase in systolic blood pressure at the age of 14 weeks compared to corresponding C57BL/6J (WT) mice with concomitant decreased expression of nNOS (0.75±0.05 WT vs. 0.43±0.11* Akita) in the PVN. Further, Akita mice had increased expression of ACE (angiotensin converting enzyme) (WT 0.34±0.04 vs. Akita 0.58±0.05*) and AT
1
R (WT 0.29±0.09 vs. Akita 0.49±0.03*) and decreased expression of ACE2 (0.27±0.03 WT vs. 0.17±0.05* Akita) and Mas receptor (WT 0.77±0.07 vs. Akita 0.46±0.02*), suggesting an imbalance in the excitatory and protective arms of RAS. Moreover, we found increased protein levels of PIN (a protein inhibitor of nNOS, known to dissociate catalytically active nNOS dimers to monomers) (WT 0.71±0.09 vs. Akita 1.75±0.08) with 72 percent decrease in dimer/monomer ratio of nNOS (WT 0.19±0.0 vs. Akita 0.11±0.04) in the PVN of Akita mice. Taken together, our studies suggest that accumulation of PIN, mediated by activation of the excitatory arm of RAS, leads to a decrease in the active dimeric form of nNOS resulting in reduced NO causing an over-activation of the sympathetic drive, leading to hypertension in DM.
1
Electrical Properties of Colonic Smooth Muscle in Spontaneously Non-Insulin-Dependent Diabetic Rats.
