Retroperitoneal adipose tissue denervation improves cardiometabolic and autonomic dysfunction in a high fat diet model.

Sympathetic vasomotor overactivity is a major feature leading to the cardiovascular dysfunction related to obesity. Considering that the retroperitoneal white adipose tissue (rWAT) is an important fat visceral depot and receives intense sympathetic and afferent innervations, the present study aimed to evaluate the effects evoked by bilateral rWAT denervation in obese rats. Male Wistar rats were fed with HFD for 8 consecutive weeks and rWAT denervation was performed at the 6th week. Arterial pressure, splanchnic and renal sympathetic vasomotor nerve activities were assessed and inflammation and the components of the renin -angiotensin system were evaluated in different white adipose tissue depots. HFD animals presented higher serum levels of leptin and glucose, an increase in arterial pressure and splanchnic sympathetic nerve activity; rWAT denervation, normalized these parameters. Pro-inflammatory cytokines levels were significantly increased, as well as RAAS gene expression in WAT of HFD animals; rWAT denervation significantly attenuated these changes. In conclusion, HFD promotes vasomotor sympathetic overactivation and inflammation with repercussions on the cardiovascular system. In conclusion, the neural communication between WAT and the brain is fundamental to trigger sympathetic vasomotor activation and this pathway is a possible new therapeutic target to treat obesity-associated cardiovascular dysfunction.

Renal denervation reduces sympathetic overactivation, brain oxidative stress, and renal injury in rats with renovascular hypertension independent of its effects on reducing blood pressure.

The underlying mechanisms by which renal denervation (RD) decreases blood pressure (BP) remain incompletely understood. In this study, we investigated the effects of ischemic kidney denervation on different sympathetic outflows, brain and renal expression of angiotensin-II receptors, oxidative stress and renal function markers in the 2-kidney, 1-clip (2K-1C) rat model. Surgical RD was performed in Wistar male rats 4-5 weeks after clip implantation. After 10 days of RD, BP, and the activity of sympathetic nerves projecting to the contralateral kidney (rSNA) and splanchnic region were partially reduced in 2K-1C rats, with no change in systemic renin-angiotensin system (RAS). To distinguish the effects of RD from the reduction in BP, 2K-1C rats were treated with hydralazine by oral gavage (25 mg/kg/day for 1 week). RD, but not hydralazine, normalized oxidative stress in the sympathetic premotor brain regions and improved intrarenal RAS, renal injury, and proteinuria. Furthermore, different mechanisms led to renal injury and oxidative stress in the ischemic and contralateral kidneys of 2K-1C rats. Injury and oxidative stress in the ischemic kidney were driven by the renal nerves. Although RD attenuated rSNA, injury and oxidative stress persisted in the contralateral kidney, probably due to increased BP. Therefore, nerves from the ischemic kidney at least partially contribute to the increase in BP, sympathetic outflows, brain oxidative stress, and renal alterations in rats with renovascular hypertension. Based on these findings, the reduction in oxidative stress in the brain is a central mechanism that contributes to the effects of RD on Goldblatt hypertension.

Control of renal sympathetic nerve activity by neurotransmitters in the spinal cord in Goldblatt hypertension.

The role of spinal cord neurons in renal sympathoexcitation remains unclear in renovascular hypertension, represented by the 2-kidney, 1-clip (2K1C) model. Thus, we aimed to assess the influence of spinal glutamatergic and AT1 angiotensin II receptors on renal sympathetic nerve activity (rSNA) in 2K1C Wistar rats. Hypertension was induced by clipping the renal artery with a silver clip. After six weeks, a catheter (PE-10) was inserted into the subarachnoid space and advanced to the T10-11 vertebral level in urethane-anaesthetized rats. The effects of intrathecally (i.t.) injected kynurenic acid (KYN) or losartan (Los) on blood pressure (BP) and rSNA were analysed over 2 consecutive hours. KYN induced a significantly larger drop in rSNA among 2K1C rats than among control (CTL) rats (CTL vs. 2K1C: -8 ±â€¯3 vs. -52 ±â€¯9 spikes/s after 120'). Los also evoked a significantly larger drop in rSNA among 2K1C rats than among CTL rats starting at 80' after administration (CTL vs. 2K1C - 80 min: -10 ±â€¯2 vs. -32 ±â€¯6∗; 100 min: -15 ±â€¯4 vs. -37 ±â€¯9∗; 120 min: -12 ±â€¯5 vs. -37 ±â€¯8∗ spikes/s). KYN decreased BP similarly in the CTL and 2K1C groups; however, Los significantly decreased BP in the 2K1C group only. We found upregulation of AT1 gene expression in the T11-12 spinal segments in the 2K1C group but no change in gene expression for AT2 or ionotropic glutamate (NMDA, kainate and AMPA) receptors. Thus, our data show that spinal ionotropic glutamatergic and AT1 receptors contribute to increased rSNA in the 2K1C model, leading to the maintenance of hypertension; however, the participation of spinal AT1 receptors seems to be especially important in the establishment of sympathoexcitation in this model. The origins of those projections, i.e., the brain areas involved in establishing the activity of spinal glutamatergic and angiotensinergic pathways, remain unclear.