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Role of renal denervation, oxidative stress and inflammation in renovascular hypertension

Grant number: 18/11221-1
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): September 01, 2018
Effective date (End): August 31, 2019
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:José Vanderlei Menani
Grantee:Mariana Ruiz Lauar
Supervisor abroad: John William Osborn Jr
Home Institution: Faculdade de Odontologia (FOAr). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
Local de pesquisa : University of Minnesota (U of M), United States  

Abstract

Renovascular hypertension affects 1 - 4% of the hypertensive population and it is the largest cause of secondary hypertension, affecting 25% to 35% of the patients with secondary hypertension (Tafur-Soto e White, 2015). Renovascular hypertension is induced experimentally by unilateral stenosis of a renal artery, which decreases renal perfusion pressure leading to renin release and also, an increase in angiotensin II production (Navar et al., 1998). The reactive oxygen species (ROS) like hydrogen peroxide are produced endogenously and may participate in intra- and extracellular signaling, including mediation of angiotensin II responses. Intracerebroventricular injection of hydrogen peroxide or the increase of endogenous hydrogen peroxide using the catalase inhibitor ATZ reduced the pressor responses to central angiotensin II in normotensive rats (Lauar et al., 2010). In renovascular hypertensive rats, subcutaneous injections of ATZ decrease de arterial pressure and the sympathetic modulation. Sympathetic vasomotor activity is significantly increased in renovascular hypertension (Haeusler et al., 1972; Brody et al., 1984; Oliveira-Sales et al., 2014). Renal denervation (DNX) has emerged as a novel therapy for resistant hypertension to drug therapy. However, the mechanisms regarding the reduction in blood pressure after DNX remain unclear. It´s known that he kidneys received projections of efferent neurons for the brain and send afferent projections to the brain (Guyenet, 2006). Presympathetic neurons in the rostral ventrolateral medulla (RVLM) and paraventricular nucleus of hypothalamus (PVN) are required for the control of sympathetic vasomotor tone and blood pressure. Studies suggest that activation of central and peripheral mechanisms during hypertension is associated with release of inflammatory mediators, represented by an increase in proinflammatory cytokines (IL-1, IL-6, TNF-±), and a decreased in anti-inflammatory cytokines (IL-10) (Shi et al., 2010a, 2010b; Sriramula et al., 2013). These cytokines could modulate neuronal activity via production of ROS, because cytokines could activate neuronal and microglial NADPH oxidase releasing ROS that modulate neuronal activity (Shi et al., 2010b) and this set of actions could contribute to maintain the hypertensive state. Thus, the aim of this new project is study the effects of the combination of total renal denervation (TRDNx) whit the systemic catalase blockade in renovascular hypertension model. We intend to clarify by which mechanisms these two approaches will be reduces the hypertension in this model. We intend also verify the role of oxidative stress and inflammation in the kidney and in central areas that could be involved in this responses.