BLOOD PRESSURE LOWERING EFFECTS OF CENTRAL TNF- BLOCKADE DEPENDS ON FUNCTIONAL LEPTIN SIGNALING

I. TUDORANCEA; Ionela Lacramioara SERBAN; D. N. ȘERBAN; C. C. CATALIN; B. I. TAMBA; R. ILIESCU

I. TUDORANCEA “Grigore T. Popa” University of Medicine and Pharmacy Iasi
Ionela Lacramioara SERBAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
D. N. ȘERBAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
C. C. CATALIN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
B. I. TAMBA “Grigore T. Popa” University of Medicine and Pharmacy Iasi
R. ILIESCU “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Keywords: OBESITY, LEPTIN, TNF-α, HYPERTENSION, BAROREFLEX SENSITIVITY

Abstract

Background: Obesity is a major independent risk factor for the development and progression of arterial hypertension. Leptin-mediated sympathoexcitation is a common phenomenon in obesity. Since leptin leads to the synthesis of Tumor Necrosis Factor (TNF)-a in the central nervous system, we hypothesized that the pathological activation of the sympathetic nervous system in obesity-associated hypertension may be mediated by central leptin-related TNF-a mechanisms. Material and methods: We compared the long-term effects of TNF-a inhibition on mean arterial blood pressure, heart rate, baroreflex sensitivity and sympathetic tone in animals with a functional leptin signaling (i.e. lean Zucker rats - LZR) and in animals insensitive to leptin (i.e. obese Zucker rats - OZR). Results: central inhibition of TNF-a in normotensive LZR significantly lowered mean arterial blood pressure, decreased sympathetic activity and improved baroreflex sensitivity but not in the OZR group. Conclusions: These findings suggest that a functionally central leptin-TNF-a signaling plays a key role in mediating the central sympathetic outflow and may represent a promising approach to ameliorate the pathophysiology of obesity related-hypertension.

Author Biographies

I. TUDORANCEA, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Morpho-functional Sciences (II). Division of Physiology
“Sf. Spiridon” County Clinical Emergency Hospital Iasi, Romania
Cardiology Clinic

Ionela Lacramioara SERBAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Morpho-functional Sciences (II). Division of Physiology

D. N. ȘERBAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Morpho-functional Sciences (II). Division of Physiology

C. C. CATALIN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Advanced Research and Development Center for Experimental Medicine (CEMEX)

B. I. TAMBA, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Morpho-functional Sciences (II). Division of Pharmacology
Advanced Research and Development Center for Experimental Medicine (CEMEX)

R. ILIESCU, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Department of Morpho-functional Sciences (II). Division of Pharmacology

References

1. Jordan J, Kurschat C, Reuter H. Arterial Hypertension. Dtsch Arztebl Int 2018; 115(33-34): 557-568.
2. Hall JE, do Carmo JM, da Silva AA, Wang Z, Hall ME. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res 2015; 116(6): 991-1006.
3. Guarino D, Nannipieri M, Iervasi G, Taddei S, Bruno RM. The role of the autonomic nervous system in the pathophysiology of obesity. Front Physiol 2017; 8: 665 / doi: 10.3389/fphys.2017.00665. eCol-lection 2017.
4. Lambert EA, Esler MD, Schlaich MP, Dixon J, Eikelis N, Lambert GW. Obesity-Associated Organ Damage and Sympathetic Nervous Activity. Hypertension 2019; 73(6): 1150-1159.
5. Valensi P. Autonomic nervous system activity changes in patients with hypertension and overweight: role and therapeutic implications. Cardiovasc Diabetol 2021; 20(1): 170 / doi: 10.1186/s12933-021-01356-w.
6. da Silva AA, do Carmo JM, Hall JE. Role of leptin and central nervous system melanocortins in obesity hypertension. Curr Opin Nephrol Hypertens 2013; 22(2): 135-140.
7. Mark AL, Agassandian K, Morgan DA, Liu X, Cassell MD, Rahmouni K. Leptin signaling in the nucleus tractus solitarii increases sympathetic nerve activity to the kidney. Hypertension 2009; 53(2): 375-380.
8. Harlan SM, Rahmouni K. PI3K signaling: A key pathway in the control of sympathetic traffic and arterial pressure by leptin. Mol Metab 2013; 2(2): 69-73.
9. Han C, Wu W, Ale A, Kim MS, Cai D. Central Leptin and Tumor Necrosis Factor-α (TNFα) in Diurnal Control of Blood Pressure and Hypertension. J Biol Chem 2016; 291(29): 15131-15142.
10. Smith MM, Minson CT. Obesity and adipokines: effects on sympathetic overactivity. J Physiol (Lond) 2012; 590(8): 1787-1801.
11. Ding L, Kang Y, Dai H-B, et al. Adipose afferent reflex is enhanced by TNFα in paraventricular nucleus through NADPH oxidase-dependent ROS generation in obesity-related hypertensive rats. J Transl Med 2019; 17(1): 256 / doi: 10.1186/s12967-019-2006-0.
12. Arnold AC, Shaltout HA, Gallagher PE, Diz DI. Leptin impairs cardiovagal baroreflex function at the level of the solitary tract nucleus. Hypertension 2009; 54(5): 1001-1008.
13. Żera T, Nowiński A, Kwiatkowski P. Centrally administered TNF increases arterial blood pressure independently of nitric oxide synthase. Neuropeptides 2016; 58: 67-72.
14. Tudorancea I, Lohmeier TE, Alexander BT, Pieptu D, Serban DN, Iliescu R. Reduced Renal Mass, Salt-Sensitive Hypertension Is Resistant to Renal Denervation. Front Physiol 2018; 9: 455 / doi:10.3389/fphys.2018.00455.
15. Abdelrahman AM, Al Suleimani YM, Ashique M, Manoj P, Ali BH. Effect of infliximab and tocili-zumab on fructose-induced hyperinsulinemia and hypertension in rats. Biomed Pharmacother 2018; 105: 182-186.
16. Sriramula S, Cardinale JP, Francis J. Inhibition of TNF in the brain reverses alterations in RAS com-ponents and attenuates angiotensin II-induced hypertension. PLoS One 2013; 8(5): e63847.
17. Iliescu R, Tudorancea I, Irwin ED, Lohmeier TE. Chronic baroreflex activation restores spontaneous baroreflex control and variability of heart rate in obesity-induced hypertension. Am J Physiol Heart Circ Physiol 2013; 305(7): H1080-H1088.
18. Oliveira-Sales EB, Toward MA, Campos RR, Paton JFR. Revealing the role of the autonomic nervous system in the development and maintenance of Goldblatt hypertension in rats. Auton Neurosci 2014; 183: 23-29.
19. Lafontan M. Fat cells: afferent and efferent messages define new approaches to treat obesity. Annu Rev Pharmacol Toxicol 2005; 45: 119-146.
20. Karczewski J, Śledzińska E, Baturo A, Jończyk I, Maleszko A, Samborski P, et al. Obesity and in-flammation. Eur Cytokine Netw 2018; 29(3): 83-94.
21. Ellulu MS, Patimah I, Khaza’ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking mecha-nism and the complications. Arch Med Sci 2017; 13(4): 851-863.
22. Yamagishi SI, Edelstein D, Du XL, Kaneda Y, Guzmán M, Brownlee M. Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A. J Biol Chem 2001; 276(27): 25096-25100.
23. Mancuso P, Canetti C, Gottschalk A, Tithof PK, Peters-Golden M. Leptin augments alveolar macro-phage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2gamma) protein expression. Am J Physiol Lung Cell Mol Physiol 2004; 287(3): L497-502.
24. Mattioli B, Straface E, Quaranta MG, Giordani L, Viora M. Leptin promotes differentiation and survival of human dendritic cells and licenses them for Th1 priming. J Immunol 2005; 174(11): 6820-6828.
25. Paz-Filho G, Mastronardi C, Franco CB, Wang KB, Wong M-L, Licinio J. Leptin: molecular mecha-nisms, systemic pro-inflammatory effects, and clinical implications. Arq Bras Endocrinol Metabol 2012; 56(9): 597-607.
26. Lee S-M, Choi H-J, Oh C-H, Oh J-W, Han J-S. Leptin increases TNF-α expression and production through phospholipase D1 in Raw 264.7 cells. PLoS One 2014; 9(7): e102373.
27. Shen J, Sakaida I, Uchida K, Terai S, Okita K. Leptin enhances TNF-alpha production via p38 and JNK MAPK in LPS-stimulated Kupffer cells. Life Sci 2005; 77(13): 1502-1515.
28. Agrawal S, Gollapudi S, Su H, Gupta S. Leptin activates human B cells to secrete TNF-α, IL-6, and IL-10 via JAK2/STAT3 and p38MAPK/ERK1/2 signaling pathway. J Clin Immunol 2011; 31(3): 472-478.
29. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993; 259(5091): 87-91.
30. Martinelli I, Tomassoni D, Moruzzi M, et al. Cardiovascular changes related to metabolic syndrome: evidence in obese zucker rats. Int J Mol Sci 2020; 21(6): 2035 / doi: 10.3390/ijms21062035.
31. Rivera L, Morón R, Sánchez M, Zarzuelo A, Galisteo M. Quercetin ameliorates metabolic syndrome and improves the inflammatory status in obese Zucker rats. Obesity (Silver Spring) 2008; 16(9): 2081-2087.
32. Iliescu R, Chade AR. Progressive renal vascular proliferation and injury in obese Zucker rats. Micro-circulation. 2010; 17(4): 250-258.
33. Satoh N, Ogawa Y, Katsuura G, et al. Sympathetic activation of leptin via the ventromedial hypothal-amus: leptin-induced increase in catecholamine secretion. Diabetes 1999; 48(9):1787-1793.
34. Rahmouni K, Morgan DA. Hypothalamic arcuate nucleus mediates the sympathetic and arterial pressure responses to leptin. Hypertension 2007; 49(3): 647-652.
35. Haynes WG. Interaction between leptin and sympathetic nervous system in hypertension. Curr Hy-pertens Rep 2000; 2(3): 311-318.
36. Shi Z, Li B, Brooks VL. Role of the paraventricular nucleus of the hypothalamus in the sympathoex-citatory effects of leptin. Hypertension 2015; 66(5): 1034-1041.
37. Yu B, Cai D. Neural Programmatic Role of Leptin, TNFα, Melanocortin, and Glutamate in Blood Pressure Regulation vs. Obesity-Related Hypertension in Male C57BL/6 Mice. Endocrinology 2017; 158(6): 1766-1775.
38. Carvalho-Galvão A, Guimarães DD, De Brito Alves JL, Braga VA. Central inhibition of tumor necro-sis factor alpha reduces hypertension by attenuating oxidative stress in the rostral ventrolateral medulla in renovascular hypertensive rats. Front Physiol 2019; 10: 491 / doi: 10.3389/fphys.2019.00491.