Afferent Renal Nerve Research Articles

The renal afferent nerves: A role in countering salt‐sensitive hypertension?

Aim We assessed 1) the efficacy of capsaicin-mediated renal afferent denervation and, 2) the role of the renal afferent nerves in countering the development of salt-sensitive hypertension. Methods: Conscious Sprague-Dawley (SD) rats, having undergone sham (S) or renal afferent nerve denervation (ADNX) (capsaicin 33mM), received IV & intra-renal (IR) infusions of bradykinin (BK) (5-40 μg/kg/min) and adenosine (A) (2-12 μg/min) followed by ICV guanabenz (50 μg) (N=5/gp). HR, MAP and natriuresis were continuously monitored. Radiotelemetered Dahl salt-sensitive (DSS) and SD rats underwent S or ADNX (N=5/group) prior to a 21-day 8% NaCl diet challenge and MAP was continuously monitored. Results: IR, but not IV, BK dose-dependently increased MAP and HR in S but not ADNX rats (BK 40 μg/kg/min; peak ΔMAP [mmHg] S: +19±3 vs ADNX: +0.6±2, P<0.0.5). IR, but not IV, adenosine evoked a dose-dependent natriuresis in S but not ADNX rats (A 12 μg/min; peak ΔUNaV [ueq/min] S: +18.7±3 vs. ADNX: +2±0.4, P<0.05). In S and ADNX rats, ICV guanabenz evoked natriuresis (peak ΔUNaV [μeq/min] S: +13.4±1 vs. ADNX: +12.8±1). ADNX exacerbated DSS hypertension (DSS 8% NaCl Day 21 ΔMAP [mmHg]; S: +30±3 vs. ADNX: +45±6, P<0.05) and evoked the development of salt-sensitivity in SD rats (SD 8% NaCl Day 21 ΔMAP [mmHg]; S: +1±2, ADNX: +14±1, P<0.05). Conclusion Capsaicin selectively removed the afferent, but not efferent renal nerves. Afferent renal denervation exacerbated DSS hypertension and evoked increased MAP in response to sodium intake in SD rats. These data suggest a critical role of the renal afferent nerves in countering the development of salt-sensitive hypertension, potentially by functioning as a sodium responsive mechanism to facilitate sodium homeostasis and blood pressure regulation.

Targeted ablation of afferent renal nerves by periaxonal capsaicin abolishes the reno‐renal reflex

Recent clinical findings report targeted renal sympathetic denervation (RDNx) as a novel therapy to treat cardiovascular diseases. However, the contribution of ablation of afferent vs. efferent nerves in mediating responses to RDNx is unclear. Foss and colleagues have reported a novel method for afferent‐specific RDNx by periaxonal application of capsaicin (CAP), which may have an anti‐hypertensive effect. However, functional confirmation of CAP remains untested. To this end, we aimed to test the ability of CAP to block the reno‐renal reflex. Male Sprague Dawley rats (275‐300g) underwent unilateral (left) CAP (n=4) or sham (n=5) procedure. Acute experimentation was performed 3‐5 days post‐operation. Under 2% isoflurane, the left femoral artery and vein were cannulated for arterial pressure (AP) measurement and saline infusion (150mM; 50ul/min), respectively. Each renal pelvis was cannulated to control pelvic pressure and collect urine. After a 90‐minute stabilization, urine flow from the right kidney was measured while the left pelvic pressure was maintained at 0 and 20mmHg for one hour. Data was averaged over each time interval and analyzed by two‐way ANOVA with a Bonferroni post‐hoc test. Data presented as change from baseline (mean+SEM). In sham rats, a 20mmHg increase in pelvic pressure increased contralateral urine flow (Δ1.8±0.5µl/min;p&lt;.05) and Na+ excretion (Δ0.40±0.16µmol/min; p&lt;.01). CAP abolished both responses (p&lt;.01; p&lt;.001). CAP had no effect on basal levels of AP, urine output or Na+ excretion. Collectively, these data provide a functional confirmation of targeted afferent renal nerve ablation by CAP treatment. Further study is underway to further elucidate the role of renal afferent nerves in cardiovascular health and disease. NIH R01 HL116476

Increased Renal Pelvic Pressure Elicits Excitatory or Inhibitory Responses in Rat Renal Afferent Nerves that is Reduced by Renal Nerve Ablation

Renal denervation by radiofrequency (RF) ablation has been reported to ameliorate resistant hypertension and other cardiovascular diseases. Many have suggested that afferent renal nerves (ARN) are ...

Cardiovascular, Metabolic and Renal T‐cell Profile of Obese C57Bl6 mice: Role of Renal Nerves

Hypertension (HTN) is a global epidemic and often occurs in concurrence with obesity and diabetes (i.e. metabolic syndrome). Recent clinical trials suggest that renal denervation (RDNX) decreases blood pressure (BP) and improves glucose metabolism in drug resistant hypertensive patients. Using a murine model we tested the hypothesis that obesity is associated with renal inflammation secondary to T cell infiltration, which activates renal sensory nerves and increases global sympathetic activity. 8‐week old C57Bl6 mice were fed either a low fat diet (LFD; 10 KCal% fat) or a high fat diet (HFD; 45 KCal% fat) for 10 weeks. Two parallel protocols were conducted. In a metabolic protocol, body weight, food intake, body composition and fasting blood glucose were measured. In a cardiovascular protocol, mice were implanted with radiotelemeters for measurement of BP. Mice on a HFD exhibited increased splenic T cells indicating peripheral inflammation, exhibited a metabolic syndrome phenotype including increased fat mass, HTN and hyperglycemia compared to LFD. RDNX but not Sham surgery after 12 weeks of HFD normalized BP (116 ± 4 in sham vs. 97 ± 6 mmHg in RDNX mice). RDNX had no effect on BP in LFD mice. Finally, RDNX had no effect on glucose metabolism as determined by glucose tolerance test. These results suggest that renal nerves play a role in obesity induced HTN but do not contribute to impaired glucose metabolism in this murine model. Future data analysis will test the hypothesis that renal inflammation drives renal afferent nerves and global sympathetic activity in obesity‐induced HTN. Supported by RO1HL116476.

The crosstalk between the kidney and the central nervous system: the role of renal nerves in blood pressure regulation.

What is the topic of this review? This review describes the role of renal nerves as the key carrier of signals from the kidneys to the CNS and vice versa; the brain and kidneys communicate through this carrier to maintain homeostasis in the body. What advances does it highlight? Whether renal or autonomic dysfunction is the predominant contributor to systemic hypertension is still debated. In this review, we focus on the role of the renal nerves in a model of renovascular hypertension. The sympathetic nervous system influences the renal regulation of arterial pressure and body fluid composition. Anatomical and physiological evidence has shown that sympathetic nerves mediate changes in urinary sodium and water excretion by regulating the renal tubular water and sodium reabsorption throughout the nephron, changes in the renal blood flow and the glomerular filtration rate by regulating the constriction of renal vasculature, and changes in the activity of the renin-angiotensin system by regulating the renin release from juxtaglomerular cells. Additionally, renal sensory afferent fibres project to the autonomic central nuclei that regulate blood pressure. Hence, renal nerves play a key role in the crosstalk between the kidneys and the CNS to maintain homeostasis in the body. Therefore, the increased sympathetic nerve activity to the kidney and the renal afferent nerve activity to the CNS may contribute to the outcome of diseases, such as hypertension.

Intrarenal bradykinin elicits reno-renal reflex sympatho-excitation and renal nerve-dependent fluid retention.

The renal sensory nerves are importantly involved in the sympathetic regulation of cardiovascular and renal function. Two reno-renal reflexes are recognized, one in which activation of renal sensory nerves elicits a renal sympatho-inhibition, and one which causes a renal sympatho-excitation and about which little is known. This study investigated the role of bradykinin (BK) in engaging an excitatory reno-renal reflex. Rats were anaesthetized (chloralose/urethane) and prepared for the measurement of renal function or renal sympathetic nerve activity (RSNA). BK was infused into the cortico-medullary border of the ipsilateral kidney and the impact on contralateral renal function and RSNA evaluated. Intrarenal infusion of BK at 3 × 10(-9) and 6 × 10(-9) g L(-1) had no effect on mean arterial pressure, at 104 ± 5 mmHg or glomerular filtration rate in either the ipsilateral or contralateral kidneys, at 4.31 ± 0.45 mL min(-1) kg(-1) . At the highest dose of BK, fractional sodium excretion (FENa) was 1.47% in the ipsilateral kidney and was significantly lower, at 0.64% (P < 0.05) in the contralateral kidney but this difference did not occur following ipsilateral renal denervation. Ipsilateral intrarenal infusion of BK at 3 × 10(-9) , 6 × 10(-9) and 1.2 × 10(-8) g L(-1) elicited dose-related increases (P < 0.05) in contralateral RSNA, reaching some 78% at the highest dose, but these responses were prevented by ipsilateral renal denervation. Intrarenal infusion of BK produced an excitatory reno-renal reflex which was expressed as a renal nerve-dependent antinatriuresis in the contralateral kidney. The findings suggest that inflammatory mediators such as BK may be important in initiating a sympatho-excitation associated with renal and cardiovascular diseases.

Role of renal sensory nerves in physiological and pathophysiological conditions.

Whether activation of afferent renal nerves contributes to the regulation of arterial pressure and sodium balance has been long overlooked. In normotensive rats, activating renal mechanosensory nerves decrease efferent renal sympathetic nerve activity (ERSNA) and increase urinary sodium excretion, an inhibitory renorenal reflex. There is an interaction between efferent and afferent renal nerves, whereby increases in ERSNA increase afferent renal nerve activity (ARNA), leading to decreases in ERSNA by activation of the renorenal reflexes to maintain low ERSNA to minimize sodium retention. High-sodium diet enhances the responsiveness of the renal sensory nerves, while low dietary sodium reduces the responsiveness of the renal sensory nerves, thus producing physiologically appropriate responses to maintain sodium balance. Increased renal ANG II reduces the responsiveness of the renal sensory nerves in physiological and pathophysiological conditions, including hypertension, congestive heart failure, and ischemia-induced acute renal failure. Impairment of inhibitory renorenal reflexes in these pathological states would contribute to the hypertension and sodium retention. When the inhibitory renorenal reflexes are suppressed, excitatory reflexes may prevail. Renal denervation reduces arterial pressure in experimental hypertension and in treatment-resistant hypertensive patients. The fall in arterial pressure is associated with a fall in muscle sympathetic nerve activity, suggesting that increased ARNA contributes to increased arterial pressure in these patients. Although removal of both renal sympathetic and afferent renal sensory nerves most likely contributes to the arterial pressure reduction initially, additional mechanisms may be involved in long-term arterial pressure reduction since sympathetic and sensory nerves reinnervate renal tissue in a similar time-dependent fashion following renal denervation.

A novel method of selective ablation of afferent renal nerves by periaxonal application of capsaicin.

Renal denervation has been shown to lower arterial pressure in some hypertensive patients, yet it remains unclear whether this is due to ablation of afferent or efferent renal nerves. To investigate the role of afferent renal nerves in arterial pressure regulation, previous studies have used methods that disrupt both renal and nonrenal afferent signaling. The present study was conducted to develop and validate a technique for selective ablation of afferent renal nerves that does not disrupt other afferent pathways. To do this, we adapted a technique for sensory denervation of the adrenal gland by topical application of capsaicin and tested the hypothesis that exposure of the renal nerves to capsaicin (renal-CAP) causes ablation of afferent but not efferent renal nerves. Renal-CAP had no effect on renal content of the efferent nerve markers tyrosine hydroxylase and norepinephrine; however, the afferent nerve marker, calcitonin gene-related peptide was largely depleted from the kidney 10 days after intervention, but returned to roughly half of control levels by 7 wk postintervention. Moreover, renal-CAP abolished the cardiovascular responses to acute pharmacological stimulation of afferent renal nerves. Renal-CAP rats showed normal weight gain, as well as cardiovascular and fluid balance regulation during dietary sodium loading. To some extent, renal-CAP did blunt the bradycardic response and increase the dipsogenic response to increased salt intake. Lastly, renal-CAP significantly attenuated the development of deoxycorticosterone acetate-salt hypertension. These results demonstrate that renal-CAP effectively causes selective ablation of afferent renal nerves in rats.

Reinnervation of renal afferent and efferent nerves at 5.5 and 11 months after catheter-based radiofrequency renal denervation in sheep.

Previous studies indicate that catheter-based renal denervation reduces blood pressure and renal norepinephrine spillover in human resistant hypertension. The effects of this procedure on afferent sensory and efferent sympathetic renal nerves, and the subsequent degree of reinnervation, have not been investigated. We therefore examined the level of functional and anatomic reinnervation at 5.5 and 11 months after renal denervation using the Symplicity Flex catheter. In normotensive anesthetized sheep (n=6), electric stimulation of intact renal nerves increased arterial pressure from 99±3 to 107±3 mm Hg (afferent response) and reduced renal blood flow from 198±16 to 85±20 mL/min (efferent response). In a further group (n=6), immediately after denervation, renal sympathetic nerve activity was absent and the responses to electric stimulation were abolished. At 11 months after denervation (n=5), renal sympathetic nerve activity and the responses to electric stimulation were at normal levels. Immunohistochemical staining for renal efferent (tyrosine hydroxylase) and renal afferent nerves (calcitonin gene-related peptide), as well as renal norepinephrine levels, was normal 11 months after denervation. Findings at 5.5 months after denervation were similar (n=5). In summary, catheter-based renal denervation effectively ablated the renal afferent and efferent nerves in normotensive sheep. By 11 months after denervation the functional afferent and efferent responses to electric stimulation were normal. Reinnervation at 11 months after denervation was supported by normal anatomic distribution of afferent and efferent renal nerves. In view of this evidence, the mechanisms underlying the prolonged hypotensive effect of catheter-based renal denervation in human resistant hypertension need to be reassessed.

The kidney-heart connection during electrical storm: from bedside back to bench.

One of the most challenging clinical pre-sentations for cardiologists is the ‘electrical storm’ of incessant ventricular tachycardia (VT). This often occurs in patients with previous myocardial infarctions or non-ischaemic cardiomyopathies, who are already on the maximally tolerated doses of cardiac medications (including β-blockers). Such patients may have already been implanted with a cardiac defibrillator (ICD) and are therefore likely to receive multiple therapies from their device. The cardiologist corrects plasma electrolytes, administers additional antiarrhythmic drugs (such as amiodarone and lidocaine) and reprograms the ICD in an attempt to suppress the storm, but ultimately many patients will require general anaesthesia and emergency ablation of their VT. This is a perilous ‘last-ditch’ procedure with limited long-term success. It may, however, stabilize the patient long enough for consideration of heart transplantation. Case reports and small case series have highlighted novel procedures aimed at reducing cardiac sympathetic drive as possible adjunct therapies in such patients. This builds on over 50 years of intense research linking cardiac sympathetic drive to arrhythmogenicity (Shen & Zipes, 2014). Even sedation or general anaesthesia in itself can be antiarrhythmic, because sympathetic hyperactivity during the electrical storm can be reinforced by chest pain from VT and ICD shocks received whilst still conscious. Recent publications have advocated stellatectomy (Schwartz, 2014), thoracic epidural anaesthesia and renal sympathetic nerve denervation (Bradfield et al. 2014) as potential approaches. In this context, the paper by Huang et al. (2014) in this issue of Experimental Physiology is of particular interest. In anaesthetized dogs following renal sympathetic denervation or a sham procedure, Huang et al. (2014) performed catheter-based measurements of ventricular refractory period and action potential duration (APD) restitution at multiple epicardial sites. This is the first publication to my knowledge to characterize ventricular electrophysiological changes in response to renal denervation. Interestingly, the flattening in the slope of the APD restitution curve, prolongation of the refractory period and reduced ability to induce APD alternans mirrors previous reports of the action of selective cardiac sympathetic stimulation on these parameters. Moreover, renal denervation reduced the incidence of ventricular arrhythmias in the hour following ligation of the left anterior descending coronary artery. The paper by Huang et al. (2014) also follows the recently published failure of renal sympathetic nerve denervation to produce a significant reduction in blood pressure in patients with resistant hypertension when compared with a sham procedure in the Symplicity HTN-3 trial (Bhatt et al. 2014). There are a number of interesting methodological differences in the approach to renal denervation taken by Huang et al. (2014) compared with that used in Symplicity HTN-3. In human subjects, renal denervation is usually undertaken via an endovascular approach using a radiofrequency ablation catheter introduced via the femoral artery. Discrete lesions are made circumferentially in a spiral pattern along both renal arteries, but unfortunately there is no way of determining that successful denervation has been achieved during the procedure. Huang et al. (2014) performed epivascular ablation via small bilateral retroperitoneal flank incisions. Furthermore, they demonstrated as evidence of successful denervation that high-frequency electrical stimulation of the adventitia no longer caused hypertension following ablation. This is a useful and novel approach, and a similar clinical end-point of success in patients is clearly needed. The fact that afferent and efferent nerves innervate the kidney through a plexus surrounding the renal arteries has long been appreciated. Renal afferent nerves are able to stimulate the hypothalamus in response to renal hypoxia and ischaemia and thereby increase global sympathetic activity. Likewise, sympathetic efferent nerves cause renin release, sodium and water retention, and through angiotensin II, reinforce sympathetic drive both centrally and by increasing catecholamine release peripherally (Singh et al. 2014). Renal denervation as a method to reduce cardiac sympathetic drive therefore appears logical, although many questions regarding this approach remain unanswered. Can a reduction in cardiac sympathetic activity following renal denervation be measured directly? Do the electrophysiological changes in APD and refractory period observed in the normal canine heart also occur in ischaemic and non-ischaemic cardiomyopathy? How long do these electrophysiological changes persist for and what are the underlying mechanisms by which they occur? In the clinical case reports of renal denervation for electrical storm, patients were already maximally β-blocked. Is the antiarrhythmic action of this procedure therefore independent of β-receptors, and if so, which other receptors or sympathetic cotransmitters play a role? This promises to be an active area of research, which may help us to identify new antiarrhythmic targets as well as refine our approach to renal denervation in patients. Readers are invited to give their opinion on this article. To submit a comment, go to: http://ep.physoc.org/letters/submit/expphysiol;99/11/1451 None declared. N.H. is a British Heart Foundation CRE Intermediate Fellow at the University of Oxford.

GW25-e0608 The effects of renal artery diameter in patients with resistant hypertension by renal sympathetic denervation

Catheter-based renal sympathetic denervation (RDN) was introduced as a novel interventional technique in recent years, which could simultaneously block the renal artery afferent and efferent nerve fibers and showed remarkable therapeutic effects in the treatment of resistant hypertension. In our

Abstract 085: The Role of Afferent and Efferent Renal Nerves in T Lymphocyte Recruitment into the Kidneys and Development of Two Models of Salt-Dependent Hypertension

Renal denervation (RDNX) attenuates hypertension (HT) in some animal models and human patients, yet the antihypertensive mechanisms involved are not known. Because it has been suggested that efferent renal nerves may cause recruitment of T lymphocytes (T cells) into the kidneys, and T cell-secreted cytokines can activate afferent neurons, we hypothesized that RDNX attenuates HT in the angiotensin II (AngII)-salt and deoxycorticosterone acetate (DOCA)-salt models by decreasing efferent renal nerve-dependent T cell trafficking to the kidneys and T cell-mediated activation of afferent renal nerves. Male Sprague-Dawley rats underwent SHAM surgery, RDNX or selective ablation of afferent renal nerves (renal-CAP) and were subjected to either AngII-salt or DOCA-salt HT. AngII-salt rats underwent SHAM, RDNX or renal-CAP (n = 8/group) and were instrumented with an IV catheter and radio-telemeter to measure mean arterial pressure (MAP). Rats were fed a 4% NaCl diet and, after a baseline period, AngII was infused IV (10 ng/kg/min) for 16 days. DOCA-salt rats were unilaterally nephrectomized and, after 2 weeks, instrumented with a radio-telemeter, subjected to SHAM (n = 5), RDNX (n = 7) or renal-CAP (n = 6) and given 0.9% saline to drink. After a baseline period, silicone pellets containing 100mg DOCA were implanted SC and rats were sacrificed 3 weeks later. Upon sacrifice, kidneys were harvested for flow cytometry to determine the number of CD4+ and CD8+ T cells in the kidneys. In AngII-salt rats, renal CD4 and CD8 T cell counts and the change in MAP from baseline (ΔMAP) were similar between groups (SHAM = 42.3 ± 6.4 mmHg, RDNX = 32.6 ± 5.9 mmHg, renal-CAP = 36.8 ± 5.0 mmHg). In DOCA-salt rats, RDNX and renal-CAP significantly attenuated ΔMAP (SHAM = 24.2 ± 3.1 mmHg, RDNX = 12.7 ± 2.4 mmHg, renal-CAP = 13.8 ± 1.7 mmHg). CD8 T cell counts in RDNX kidneys were significantly lower than SHAM (p &lt; 0.01) and trended lower than renal-CAP. CD4 T cell counts in RDNX kidneys were significantly lower than renal-CAP (p &lt; 0.05) and trended lower than SHAM. These data show that renal nerves do not contribute to AngII-salt HT, but suggest that afferent renal nerves contribute to DOCA-salt HT and that this may be T cell-mediated and dependent on efferent renal nerves. Funding: R01 HL116476-01.

Abstract 084: Activation Of Trpv1-expressing Renal Sensory Nerves With N-oleoyldopamine Attenuates High Fat Diet-induced Impairment In Renal Function

Renal injury occurs in obesity. Accumulating evidence indicates that activation of the transient receptor potential vanilloid 1 (TRPV1) protects tissues from injury albeit the mechanisms are largely unknown. We test the hypothesis that high fat diet (HFD) intake impairs afferent renal nerves expressing TRPV1 channels, leading to increased renal sympathetic nerve activity (RSNA), decreased renal function, and hypertension, and that chronic activation of TRPV1 positive afferent renal nerves attenuates HFD-induced impairment. N-oleoyldopamine (OLDA, 1 ng/kg, daily), a selective TRPV1 agonist, was administrated intrathecally (T8-L3) via a indwelled catheter to chronically activate TRPV1 positive afferent renal nerves in rats fed a HFD or normal fat diet (Con) for 8 weeks. HFD decreased renal TRPV1 expression and afferent renal nerve activity (ARNA, Con: 133±8, Con+OLDA: 127±15, HFD: 84±5, HFD+OLDA: 115±7, p&lt;0.05) in response to intra-pelvis perfusion of capsaicin (4 μM, 3 min, 20 ml/min), a selective TRPV1 agonist, which were prevented by OLDA. HFD increased RSNA responses to intrathecal injection of muscimol (3 nmol/kg), a GABA-A receptor agonist, and urinary norepinephrine levels, which were prevented by OLDA. HFD decreased creatinine clearance and increased urinary albumin levels, which were prevented by OLDA (Creatinine clearance, Con: 0.52±0.09, Con+OLDA: 0.54±0.12, HFD: 0.24±0.04, HFD+OLDA: 0.40±0.06 ml/min/100 gbwt, p&lt;0.05). HFD increased levels of collagen deposition, connective tissue growth factor (CTGF), and matrix metalloproteinase-2 (MMP-2) in the kidney, which were prevented by OLDA. HFD increased systolic blood pressure by the week of 6 after HFD, which was prevented by OLDA. Thus, HFD impairs TRPV1-positive afferent renal nerves, increases renal sympathetic nerve activity, and leads to renal injury and hypertension. Segment-specific intrathecal injection of OLDA protects against HFD-induced impairment in afferent renal nerves and prevents HFD-induced renal injury and hypertension. Our data illustrate that preservation of TRPV1 positive afferent renal nerves may be a therapeutic strategy in preventing obesity- or type 2 diabetes-induced renal injury and hypertension.

Abstract 275: High Fat Diet-induced Decreases In Insulin Signaling In Afferent Renal Nerves Are Prevented By Intrathecal Injection Of Metformin In Rats

Metformin, an anti-type 2 diabetic agent that increases insulin sensitivity in target tissues, has been suggested having neuroprotective effects. Our previous data showed that metformin protects against high fat diet (HFD)-induced impairment in renal afferent nerves that express the transient receptor potential vanilloid 1 (TRPV1) channels, and prevents HFD-induced renal functional deterioration and hypertension. However, mechanisms of metformin-mediated neuroprotection are largely unknown. This study tests the hypothesis that HFD impairs insulin signaling in afferent renal nerves, which is prevented by metformin via the pathway of IRS-1-tyr, AMPK, and GLUT-1/3. Metformin (1 ng/kg, daily intrathecal injection via indwelled catheters to segments T8-L3 supplying the kidneys) or vehicle was given to rats fed a HFD or normal fat diet (Con) for 8 weeks. Immunohistochemical staining showed that insulin receptor substrate-1 phosphorylated with serine (p-IRS-1-ser), insulin receptor substrate-1 phosphorylated with tyrosine (p-IRS-1-tyr), phosphorylated AMP-activated protein kinase (p-AMPK), glucose transporter 1 (GLUT-1), and GLUT-3 were expressed in dorsal root ganglia (DRG). Levels of p-IRS-1-ser were increased by HFD but decreased by metformin in Con rats, and HFD-induced increases in p-IRS-1-ser were prevented by metformin. Levels of p-IRS-1-tyr, p-AMPK, and the trafficking of GLUT-1 and GLUT-3 from cytoplasma to cell membrane in DRG were decreased by HFD but increased by metformin in Con rats, and HFD-induced decreases in these parameters were prevented by metformin (p-IRS-1-tyr, Con: 0.23±0.02, Con+Met: 0.34±0.04, HFD: 0.14±0.02, HFD+Met: 0.22±0.03, p&lt;0.05). Afferent renal nerve activity (ARNA) in response to insulin perfusion into the renal pelvis was decreased by HFD but enhanced by metformin in Con rats, and HFD-induced decreases in ARNA was prevented by metformin. Our data showed that HFD decreases insulin signaling in afferent renal nerves, which is prevented by metformin injected intrathecally to segments innervating kidneys. These data indicate that metformin may constitute neuroprotecitve effects via improving insulin signaling in afferent renal nerves via activation of the pathway of IRS-1-tyr, AMPK, and GLUT-1/3.

Renal denervation: a new therapeutic approach for resistant hypertension

Objective To review the advances in studies on renal denervation. Data sources References concerning renal denervation and resistant hypertension cited in this review were collected from PubMed published in English and those of renal denervation devices from official websites of device manufacturers up to January 2014. Study selection Articles with keywords “renal denervation” and “resistant hypertension” were selected. Results Renal and systemic sympathetic overactivity plays an important role in pathology of hypertension as well as other diseases characterized by sympathetic overactivity. Renal denervation is a new, catheter based procedure to reduce renal and systemic sympathetic overactivity by disruption of renal sympathetic efferent and afferent nerves through radiofrequency or ultrasound energy delivered to the endoluminal surface of both renal arteries. Although several studies have shown the efficacy and safety of renal denervation in the treatment of resistant hypertension and the potential benefit of the procedure in other diseases, Symplicity HTN 3 study, the most rigorous clinical trial of renal denervation to date, failed to meet its primary endpoint. The procedure also has other limitations such as the lack of long term, efficacy and safety data and the lack of the predictors for the blood pressure lowering response and nonresponse to the procedure. An overview of current renal denervation devices holding Conformité Européenne mark is also included in this review. Conclusions Renal denervation is a promising therapeutic approach in the management of resistant hypertension and other diseases characterized by sympathetic overactivity. In its early stage of clinical application, the efficacy of the procedure is still controversial. Large scale, blind, randomized, controlled clinical trials are still necessary to address the limitations of the procedure.

Progression of kidney injury and cardiac remodeling in obese spontaneously hypertensive rats: the role of renal sympathetic innervation.

Hypertension and metabolic syndrome (MetS) are associated with increased sympathetic activation possibly contributing to the progression of renal damage and cardiac remodeling. Renal sympathetic denervation (RDN) decreases sympathetic renal efferent and afferent nerve activity. Obese spontaneously hypertensive rats (SHRs-ob) were subjected to RDN at the age of 34 weeks (SHRs-ob + RDN) and were compared with sham-operated SHRs-ob and their normotensive lean controls (Ctrs). Blood pressure was measured by telemetry. Kidney and heart function were determined by magnetic resonance imaging (MRI). Renal and cardiac remodeling were characterized by immunohistochemical analyses. Animals were killed at the age of 48 weeks. In SHRs-ob, RDN attenuated the progressive increase in blood pressure and preserved a mean blood pressure of 156±7mm Hg compared with 220±8mm Hg in sham-operated SHRs-ob at 100 days after RDN, whereas heart rate, body weight, and metabolic parameters remained unchanged. Renal catecholamine and tyrosine hydroxylase levels were significantly reduced after RDN, suggesting effective renal denervation. Progression of renal dysfunction as characterized by increased urinary albumin/creatinine ratio and reduced glomerular filtration rate were attenuated by RDN. In SHRs-ob, renal perfusion was significantly reduced and normalized by RDN. Cardiac fibrosis and cardiac diastolic dysfunction measured by MRI and invasive pressure measurements were significantly attenuated by RDN. In SHRs-ob, progressive increase in blood pressure and progression of renal injury and cardiac remodelling are mediated by renal sympathetic activation as they were attenuated by RDN.

Renal sympathetic denervation attenuates the ventricular substrate and electrophysiological remodeling in dogs with pacing-induced heart failure

Catheter-based renal artery ablation selectively reduces both renal sympathetic efferent and afferent nerve activity and causes renal sympathetic denervation (RSD) [1]. Some clinical trials and animal experiments have suggested that RSD could decrease the RAAS activity [2], and further has great potential in the treatment of heart failure (HF) [3]. Whether RSD can attenuate ventricular arrhythmia (VA) and ventricular substrate remodeling induced by catheter-based renal artery ablation is unclear.

Renal denervation--implications for chronic kidney disease.

Catheter-based renal denervation to treat patients with resistant hypertension and chronic kidney disease (CKD) has generated considerable interest. Data from the majority of, but not all, observational studies and randomized controlled trials suggest that the procedure does not impair renal function and can effectively reduce office and ambulatory blood pressure in patients with primary hypertension. The putative beneficial effects of renal denervation seem to result from the interruption of renal efferent and afferent nerves. In patients with resistant hypertension and CKD, interruption of afferent reflexes might lead to a reduction in global sympathetic tone. The subsequent sustained reduction in blood pressure is expected to slow the progression of renal disease. However, renal denervation might also improve glucose metabolism, increase insulin sensitivity and reduce renal inflammation, with renoprotective effects in patients with CKD. Additional large randomized controlled trials of renal denervation in hypertensive and normotensive patients with CKD are required to precisely define the clinical value of the procedure in this population.

Sustained sympathetic and blood pressure reduction 1 year after renal denervation in patients with resistant hypertension.

Renal denervation (RDN) reduces muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in resistant hypertension. Although a persistent BP-lowering effect has been demonstrated, the long-term effect on MSNA remains elusive. We investigated whether RDN influences MSNA over time. Office BP and MSNA were obtained at baseline, 3, 6, and 12 months after RDN in 35 patients with resistant hypertension. Office BP averaged 166±22/88±19 mm Hg, despite the use of an average of 4.8±2.1 antihypertensive drugs. Baseline MSNA was 51±11 bursts/min ≈2- to 3-fold higher than the level observed in healthy controls. Mean office systolic and diastolic BP significantly decreased by -12.6±18.3/-6.5±9.2, -16.1±25.6/-8.6±12.9, and -21.2±29.1/-11.1±12.9 mm Hg (P<0.001 for both systolic BP and diastolic BP) with RDN at 3-, 6-, and 12-month follow-up, respectively. MSNA was reduced by -8±12, -6±12, and -6±11 bursts/min (P<0.01) at 3-, 6-, and 12-month follow-up. The reduction in MSNA was maintained, despite a progressive fall in BP over time. No such changes were observed in 7 control subjects at 6-month follow-up. These findings confirm previous reports on the favorable effects of RDN on elevated BP and demonstrate sustained reduction of central sympathetic outflow ≤1-year follow-up in patients with resistant hypertension and high baseline MSNA. These observations are compatible with the hypothesis of a substantial contribution of afferent renal nerve signaling to increased BP in resistant hypertension and argue against a relevant reinnervation at 1 year after procedure.

Central projections of sodium‐sensitive afferent renal nerves in rats (687.3)

Renal denervation is reported to treat resistant essential hypertension. Many suggest that afferent renal nerves (ARN) are responsible for the full expression of hypertension. We hypothesized that osmosensitive ARN activate sites in the CNS that contribute to hypertension by evoking excessive sympathetic nerve activity. To determine the central projections, a dual lumen cannula was implanted through the left ureter into the renal pelvis of the rat. Several days later, renal pelvic afferents were bathed with different concentrations of NaCl (20, 308 and 500 mEq/L) using a push‐pull perfusion for 2 hrs while recording arterial pressure in conscious rats. Activation of CNS sites was identified using immunohistochemical detection of c‐Fos protein and compared to controls (no infusion or denervation). Many sites were dose‐dependently stimulated in response to intrarenal infusion of NaCl. These included the nucleus tractus solitarius, area postrema, parabrachial nucleus, paraventricular hypothalamus, and other areas. The results indicate that stimulation of osmosensitive ARN leads to activation of central autonomic sites involved in the regulation of sympathetic outflow. Thus, this work identifies likely sites mediating ARN‐induced sympathoexcitation contributing to the pathogenesis of hypertension.Grant Funding Source: Supported by USPHS HL25449 (ADL) and DA017371 (MMK).