Downregulation of Neuronal Nitric Oxide Synthase (nNOS) Within the Paraventricular Nucleus in Ins2-type-1 Diabetic Mice Contributes to Sympatho-excitation

Overview

Journal Nitric Oxide

Publisher Elsevier

Date 2024 Nov 9

PMID 39521242

Authors

Tapan A Patel

Lie Gao

Shane H Boomer

Xuefei Liu

Kaushik P Patel

Hong Zheng

Affiliations

Soon will be listed here.

Abstract

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 Ins2Akita (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.

References

Guix F, Uribesalgo I, Coma M, Munoz F . The physiology and pathophysiology of nitric oxide in the brain. Prog Neurobiol. 2005; 76(2):126-52. DOI: 10.1016/j.pneurobio.2005.06.001. View

Perin P, Maule S, Quadri R . Sympathetic nervous system, diabetes, and hypertension. Clin Exp Hypertens. 2001; 23(1-2):45-55. DOI: 10.1081/ceh-100001196. View

Buttler L, Ribeiro I, Ferreira-Neto H, Antunes V . Angiotensin II acting on PVN induces sympathoexcitation and pressor responses via the PI3K-dependent pathway. Auton Neurosci. 2016; 198:54-8. DOI: 10.1016/j.autneu.2016.06.006. View

Zhang L, Xiong X, Fan Z, Gan X, Gao X, Zhu G . Involvement of enhanced cardiac sympathetic afferent reflex in sympathetic activation in early stage of diabetes. J Appl Physiol (1985). 2012; 113(1):47-55. DOI: 10.1152/japplphysiol.01228.2011. View

Rosengard-Barlund M, Bernardi L, Fagerudd J, Mantysaari M, Af Bjorkesten C, Lindholm H . Early autonomic dysfunction in type 1 diabetes: a reversible disorder?. Diabetologia. 2009; 52(6):1164-72. DOI: 10.1007/s00125-009-1340-9. View

Lo C, Liu F, Shi Y, Maachi H, Chenier I, Godin N . Dual RAS blockade normalizes angiotensin-converting enzyme-2 expression and prevents hypertension and tubular apoptosis in Akita angiotensinogen-transgenic mice. Am J Physiol Renal Physiol. 2011; 302(7):F840-52. PMC: 3340935. DOI: 10.1152/ajprenal.00340.2011. View

Kinugawa T, Ogino K, Kitamura H, Saitoh M, Omodani H, Osaki S . Catecholamines, renin-angiotensin-aldosterone system, and atrial natriuretic peptide at rest and during submaximal exercise in patients with congestive heart failure. Am J Med Sci. 1996; 312(3):110-7. DOI: 10.1097/00000441-199609000-00003. View

Klatt P, Schmidt K, Lehner D, Glatter O, Bachinger H, Mayer B . Structural analysis of porcine brain nitric oxide synthase reveals a role for tetrahydrobiopterin and L-arginine in the formation of an SDS-resistant dimer. EMBO J. 1995; 14(15):3687-95. PMC: 394443. DOI: 10.1002/j.1460-2075.1995.tb00038.x. View

Chachlaki K, Prevot V . Nitric oxide signalling in the brain and its control of bodily functions. Br J Pharmacol. 2019; 177(24):5437-5458. PMC: 7707094. DOI: 10.1111/bph.14800. View

10.

Clapp K, Peng H, Jenkins G, Ford M, Morishima Y, Lau M . Ubiquitination of neuronal nitric-oxide synthase in the calmodulin-binding site triggers proteasomal degradation of the protein. J Biol Chem. 2012; 287(51):42601-10. PMC: 3522261. DOI: 10.1074/jbc.M112.412494. View

11.

Schuman E, Madison D . Nitric oxide and synaptic function. Annu Rev Neurosci. 1994; 17:153-83. DOI: 10.1146/annurev.ne.17.030194.001101. View

12.

Sharma N, Llewellyn T, Zheng H, Patel K . Angiotensin II-mediated posttranslational modification of nNOS in the PVN of rats with CHF: role for PIN. Am J Physiol Heart Circ Physiol. 2013; 305(6):H843-55. PMC: 3761348. DOI: 10.1152/ajpheart.00170.2013. View

13.

Wang S, Lin K, Chien S, Huang L, Hsu C, Tain Y . RNA silencing targeting PIN (protein inhibitor of neuronal nitric oxide synthase) attenuates the development of hypertension in young spontaneously hypertensive rats. J Am Soc Hypertens. 2013; 8(1):5-13. DOI: 10.1016/j.jash.2013.07.010. View

14.

Zucker I, Wang W, Pliquett R, Liu J, Patel K . The regulation of sympathetic outflow in heart failure. The roles of angiotensin II, nitric oxide, and exercise training. Ann N Y Acad Sci. 2001; 940:431-43. View

15.

Dunbar A, Kamada Y, Jenkins G, Lowe E, Billecke S, Osawa Y . Ubiquitination and degradation of neuronal nitric-oxide synthase in vitro: dimer stabilization protects the enzyme from proteolysis. Mol Pharmacol. 2004; 66(4):964-9. DOI: 10.1124/mol.104.000125. View

16.

Oak J, Cai H . Attenuation of angiotensin II signaling recouples eNOS and inhibits nonendothelial NOX activity in diabetic mice. Diabetes. 2006; 56(1):118-26. DOI: 10.2337/db06-0288. View

17.

Jaffrey S, Snyder S . PIN: an associated protein inhibitor of neuronal nitric oxide synthase. Science. 1996; 274(5288):774-7. DOI: 10.1126/science.274.5288.774. View

18.

Brands M, Fitzgerald S . Blood pressure control early in diabetes: a balance between angiotensin II and nitric oxide. Clin Exp Pharmacol Physiol. 2002; 29(1-2):127-31. DOI: 10.1046/j.1440-1681.2002.03619.x. View

19.

Zimpelmann J, Kumar D, Levine D, Wehbi G, Imig J, Navar L . Early diabetes mellitus stimulates proximal tubule renin mRNA expression in the rat. Kidney Int. 2000; 58(6):2320-30. DOI: 10.1046/j.1523-1755.2000.00416.x. View

20.

Li Y, Cornish K, Patel K . Alteration of NMDA NR1 receptors within the paraventricular nucleus of hypothalamus in rats with heart failure. Circ Res. 2003; 93(10):990-7. DOI: 10.1161/01.RES.0000102865.60437.55. View