Over recent years, there has been much interest in the mechanisms that influence sympathetic activity, as excessive sympathetic drive is involved in the pathophysiology of hypertension, heart failure and kidney disease. Much of the increased sympathetic tone in these conditions is directed toward the kidney, where it regulates renin release, glomerular filtration rate, renal tubular sodium reabsorption and renal pressure natriuresis. This has led to the concept of ‘neurogenic hypertension’  and the development of nerve ablation modalities that directly interrupt renal sympathetic nerve activity (RSNA) to lower blood pressure.
The kidney is densely innervated with both efferent adrenergic and somatic afferent neurons . Efferent renal sympathetic nerve activity reflects the integration of a number of sensory inputs arising from the kidney itself as well as the brain and other regions of the body such as the heart, skeletal muscle, liver and spleen. The innervated effector units of the kidney, including the tubules, the vasculature and the renin-containing juxtaglomerular granular cells, regulate the kidney's homeostatic control of body fluid volume . Increases in sympathetic outflow to the kidney activate a coordinated response involving: decreased sodium and water excretion from increased reabsorption throughout the nephron; decreased renal blood flow and glomerular filtration rate due to constriction of the renal vasculature; and increased activity of the renin–angiotensin–aldosterone system triggered by increased renin release. Increased RSNA can also indirectly increase renal sodium and water reabsorption and constriction of renal vasculature via the effects of angiotensin II (Ang II) at the Ang II type-I (AT1) receptor, which is located on the tubular and vascular segments of the nephron .
Together, the afferent and efferent nerves of the kidney form the renorenal reflex, a negative feedback system for the physiological control of renal function . Alterations in efferent RSNA tonically modulate the responsiveness of afferent sensory nerves in the renal pelvic wall to maintain body fluid and sodium homeostasis. This is clearly evident under a high-sodium state when increased afferent nerve activity decreases efferent sympathetic tone to facilitate renal sodium excretion. Conversely, in low-sodium states, altered afferent signaling results in an increase in efferent RSNA and sodium retention.
THE KIDNEY IN NEUROGENIC HYPERTENSION
Neurogenic hypertension refers to a variant of essential hypertension that is primarily due to the activation of the sympathetic nervous system. Clinical measurements of regional sympathetic nerve activity (norephinephrine spillover and microneurography) have revealed a common pattern of increased sympathetic outflow to the heart, kidneys and skeletal muscle vasculature, particularly in younger patients with essential hypertension [6,7]. Notably, there is a disproportionate rise in sympathetic outflow to the heart and kidneys, with approximately half of the increase in norepinephrine being accounted for by increased sympathetic outflow to these organs . Evidence that sympathoactivation contributes to neurogenic forms of hypertension is further supported by the therapeutic response to sympatholytics and adrenergic antagonists. More recently, interventions that directly interrupt renal efferent and afferent signaling highlight a renal component in some forms of neurogenic hypertension.
Although the mechanistic determinants for the increased sympathetic tone in neurogenic hypertension remain elusive, available data suggest that the impairment of the reflex-induced inhibition of efferent RSNA may be an important underlying factor. In spontaneously hypertensive rats, Kopp et al. recently demonstrated that the impairment of the renorenal reflex is related to reduced responsiveness of the renal pelvic sensory nerves to norepinephrine by a mechanism involving increased activation of renal α2-adrenoreceptors and AT1 receptors. This builds on their earlier work in Sprague-Dawley rats, which showed that dietary sodium alters the responsiveness of the renal sensory nerves to reflex-induced changes in efferent RSNA, and that these changes involved the modulation of norepinephrine-mediated activation of α2-adrenoreceptors . Interestingly, α2-adrenoreceptor density in renal tissue is higher in spontaneously hypertensive rats than in wild-type rats and its expression increases in parallel with dietary sodium intake and arterial pressure .
FACTORS INVOLVED IN THE REGULATION OF RENAL SYMPATHETIC NERVE ACTIVITY
Pathophysiological mechanisms underlying the increased renal sympathetic tone in neurogenic hypertension are likely to be multifactorial in origin and vary across the clinical spectrum of hypertensive states. Some of the most important factors contributing to RSNA include the renin–angiotensin system, obesity, leptin and cardiovascular baroreceptors.
It has long been proposed that Ang II plays a functional role in the development of hypertension and augmentation of RSNA. In addition to the peripheral actions of Ang II on volume retention and peripheral resistance, Ang II can act centrally to increase sympathetic nerve activity. AT1 receptors have been identified in many regions of the brain, particularly in those nuclei that are responsible for cardiovascular control and sympathetic outflow . Increased sympathetic nerve activity stimulates renin release from the juxtaglomerular cells and subsequent Ang II formation, thereby representing another mechanism by which the kidney may contribute to generalized sympathoexcitation. Furthermore, Ang II can directly act at the level of renal sympathetic nerve terminals to enhance norepinephrine release.
Despite evidence to suggest that RSNA and the renin–angiotensin system work to amplify each other's action, there have been conflicting reports on the role that Ang II plays in the development of neurogenic hypertension. Initially, delayed development of hypertension following renal denervation in animal models supported a role of RSNA in Ang II-induced hypertension . However, other studies have demonstrated that increases in arterial pressure with Ang II infusion were associated with concomitant decreases in direct  and indirect measurements of RSNA . As recently reviewed , part of the uncertainty in this area arises from the diversity of experimental protocols, specifically a lack of understanding with regards to Ang II dosing and imprecise measurements of sympathetic activity. High plasma levels of Ang II can cause vasoconstriction and subsequent increases in blood pressure can, in turn, cause sympathoinhibition via the arterial baroreflex. In the past 12 months, two studies involving direct measurements of RSNA have helped to clarify the role of Ang II in sympathetic activation. Moretti et al.[17▪▪] showed that low dose Ang II treatment for 3 months in rabbits produced a modest rise in blood pressure (16%) and a marked increase in RSNA at rest (+43%), but with no change in baroreflex gain. In another study involving direct measurements of RSNA and low-dose Ang II administration, Guild et al.[18▪] also demonstrated slow increases in arterial pressure in response to Ang II treatment in rabbits, which was accompanied by a delayed increase in RSNA. These two highlighted studies suggest that minimizing sympathoinhibition with low-dose Ang II treatment may lead to chronic elevations in RSNA and blood pressure. Of note, this experimental setting may more closely reflect the human setting.
The kidney has long been suspected of playing a role in the development of obesity-related hypertension. Obesity is associated with increased activation of the renin–angiotensin and sympathetic nervous systems, greater extracellular fluid volume and cardiac output, and increased sodium tubular reabsorption, all of which are capable of increasing blood pressure . Direct sympathetic nerve recordings and norepinephrine spillover from sympathetic nerves suggest regional specificity in obese hypertensive patients, with increased sympathetic outflow to the kidneys and skeletal muscle vasculature, but reduced outflow to the heart . Although studies suggest that sympathetic activity increases in parallel with adiposity [21,22], there remains debate over whether sympathetic activation is a cause or consequence of obesity .
Recent animal studies suggest that obesity precedes and gives rise to sympathetic excitation and hypertension. On account of observed increases in RSNA and mean arterial pressure after high-fat feeding in mice and rats , it was presumed that RSNA preceded the increase in mean arterial pressure. However, a limitation of mouse models is that RSNA cannot be measured in conscious animals and, therefore, the functional significance of increased RSNA can only be inferred from a specific point in time. Two recent studies that applied continuous measurements of the sympathetic nervous system do suggest such a role in the development of obesity-related hypertension. In rabbits instrumented for telemetric recording of RSNA and arterial pressure, Armitage et al.[25▪▪] showed increases in mean arterial pressure, heart rate and RSNA as early as 1 week after starting a high-fat diet and well before the onset of frank obesity. Mean arterial pressure and body weight continued to increase over 3 weeks of high-fat feeding, whereas heart rate and RSNA did not change further. In another study, Muntzel et al. demonstrated that a cafeteria diet produced modest nonsignificant increases in weight in female Wistar rats, which was accompanied by a doubling of brown and white adipose tissue. The increase in fat mass was accompanied by increases in lumbar sympathetic nerve activity, which became significant by day 12. Although Muntzel et al. did not measure changes in RSNA and used a different animal model, both highlighted studies demonstrated increases in sympathetic nerve activity as early as 7–12 days and relative increases in sympathetic activity were similar (∼50%).
The adipose tissue-derived hormone leptin has been suggested as a potential candidate linking obesity with sympathetic overactivation and hypertension. In the high-fat feeding studies by Muntzel and Armitage [25▪▪,26], leptin levels increased in parallel with sympathetic nerve activity and obesity. Leptin receptors have a wide distribution throughout the brain, including the hypothalamus, which has received interest for its role in activating the sympathetic nervous system . Intracerebroventricular administration of leptin in rabbits has been shown to increase mean arterial pressure and RSNA, and this relationship is further augmented by obesity . Hilzendeger et al.[29▪] demonstrated that the intracerebroventricular administration of losartan, an angiotensin receptor blocker, selectively inhibited leptin-mediated increases in RSNA, suggesting that the renin–angiotensin system may also play a facilitatory role in activation of RSNA by leptin. However, it should be acknowledged that in rodents the sympathetic system also exercises regulatory feedback inhibition of leptin release, which has not been supported in human studies .
In addition to its central actions, recent evidence suggests that leptin also influences the adipose afferent and enteroendocrine afferent reflexes. Chemical stimulation of white adipose tissue has been shown to activate the paraventricular nucleus (adipose afferent reflex), resulting in increases in RSNA and blood pressure in normal rats. However, Xiong et al.[31▪] recently demonstrated that this response was attenuated following injection of a leptin-antagonist into white adipose tissue, and was more pronounced in obese hypertensive rats than controls. How et al. also demonstrated that the renal sympathoinhibitory reflex response to stomach-derived gastric leptin is impaired with high-fat feeding and obesity, possibly by a disturbance in vagally mediated sympathetic afferent pathways involving activation of cholecystokinin receptors.
Cardiac stretch receptors in the afferent arm of the baroreflex sense changes in arterial pressure and transmit the information centrally to modulate efferent sympathetic outflow to end-target organs (i.e. kidney, vascular beds, heart). Accumulating evidence suggests that baroreflex control of RSNA is shifted toward a higher blood pressure in hypertension. Although the mechanisms responsible for these changes are not fully understood, Yamamoto et al. recently showed in rats that chronic intermittent hypoxia, which is a model of arterial hypoxemia that occurs during sleep apnea, shifted the arterial pressure–RSNA relationship rightward (by 10 mmHg approximately) compared with controls. Studies also suggest the sensitivity of RSNA responses to baroreflex changes may be impaired in obesity. Fardin et al. recently demonstrated that the sensitivity of RSNA responses to chemically induced blood pressure changes was impaired following weight gain in high-fat fed rats.
The brain acts as the control center for the neuromodulation of sympathetic outflow. An appropriate output of RSNA is determined from somatosensory information and visceral inputs to the brain, as well as multiple neurohumoral factors, which reach their receptors via penetration through the blood–brain barrier or local synthesis. Some of the neurohumoral factors that have been found to produce renal sympathetic activation after administration directly into the central nervous system include Ang II, vasopressin, ghrelin, neuropeptide Y, leptin and the cytokine TNF-α [26,28,35–40]. The major regions that are involved in sympathetic outflow include the rostral ventrolateral medulla, the hypothalamus and the nucleus of the solitary tract . Direct recordings of sympathetic activity and anatomical tracing of circuits within the central nervous system suggest that there is regional specificity, with separate groups of neurons being association with the regulation of sympathetic outflow to specific organs . Furthermore, some evidence indicates that neurohumoral factors can have different (e.g. excitatory or inhibitory) consequences depending on the site of action within the brain . Clearly, central pathways involved in the regulation of sympathetic outflow to the kidneys, and other organs, are highly complex and remain to be fully elucidated.
THERAPEUTIC EFFECTS OF SYMPATHOINHIBITORY INTERVENTIONS
Recently introduced nonpharmacologic therapeutic interventions aimed at reducing sympathetic nerve activity have shown promise in the treatment of hypertension, particularly resistant or difficult to control hypertension. Renal denervation and carotid baroreceptor stimulation represent two nonpharmacologic approaches, which achieve sympathoinhibition through transcatheter ablation of both afferent and efferent renal nerves or through the stimulation of arterial baroreceptors.
The efficacy and safety of renal denervation in resistant hypertensive patients was reviewed recently in a meta-analysis [44▪▪]. A total of 12 studies with 561 patients were included and stratified according to the nature of the study design (control vs. uncontrolled). In the controlled studies, mean blood pressure was 28.9/11.0 (systolic/diastolic) mmHg lower when compared with medically treated patients at 6 months (P < 0.0001 for both). In uncontrolled studies, mean blood pressure decreased by 25.0/10.0 mmHg at 6 months when compared with predenervation values (P < 0.0001 for both). All studies demonstrated a consistent blood pressure lowering effect, regardless of study design and the catheter employed. Furthermore, few adverse events were reported (one renal artery dissection and four femoral pseudoaneurysms), suggesting that renal denervation may be a well tolerated and efficacious option for the treatment of resistant hypertension.
Renal denervation has led to a growing interest in the function of efferent and afferent renal nerves. A clearcut reduction in renal norepinephrine spillover has been demonstrated with renal denervation . Demonstrating a contribution of afferent renal pathways in the development of hypertension is difficult, but is supported by demonstrated reductions in muscle sympathetic nerve activity (MSNA) and whole-body norepinephrine spillover following renal denervation . Recently, Hering et al. showed that renal denervation in resistant hypertension patients reduced blood pressure and decreased single-unit and multiunit MSNA, with significant changes in several properties of single-unit firing patterns (firing rate, firing probability and firing incidence). Although these results support a role of afferent renal pathways in generalized sympathetic activity, it is possible that the kidney may play a role in other mediating pathways, that is, reduction in renin release and subsequent diminished modulation of central effects by Ang II and others.
The high prevalence of obstructive sleep apnea in patients with drug-resistant hypertension, renal failure  and nonobese individuals with heart failure has led researchers to speculate whether nocturnal fluid-volume shifts, possibly mediated by increases in RSNA, may play a role in the pathogenesis of sleep apnea. In support of this hypothesis, Witkowski et al. recently demonstrated improvements in blood pressure and a reduction in the apnea–hypopnea index in eight of 10 patients with sleep apnea and resistant hypertension at 6 months following renal denervation. Although the improvement in obstructive sleep apnea was an unexpected finding, these results suggest that renal denervation might improve sleep quality as well as blood pressure.
Other sympathetically driven diseases, such as diabetes mellitus and polycystic ovary syndrome (PCOS), may also prove to be future targets for this therapy. Witkowski et al. demonstrated reductions in 2-h plasma glucose and hemoglobin A1c at 6 months postrenal denervation. In another study, Mahfoud et al. demonstrated reductions in blood pressure and fasting concentrations of glucose, insulin and C-peptide at 3 and 6 months after renal denervation. Furthermore, the homeostasis model assessment of insulin resistance was significantly reduced. As insulin resistance, hypertension and obesity are commonly associated with PCOS, the effects of renal denervation in two obese PCOS women with hypertension were recently reported . In addition to modest reductions in blood pressure, treatment reduced MSNA and norepinephrine spillover, and improved insulin sensitivity as measured by euglycemic hyperinsulinemic clamp.
Baroreflex activation therapy
The safety and efficacy of carotid baroreflex activation therapy (BAT) in patients with resistant hypertension was evaluated in the Rheos Pivotal Trial . In this randomized, placebo-controlled, double-blind study, 265 patients were randomized in a 2 : 1 ratio to commence BAT after 1 month or BAT after 6 months. At 12 months, the mean systolic blood pressure decrease with BAT was 25 mmHg, with equivalent reductions observed in the group who had deferred BAT. Significant procedural complications, including surgical complications and nerve injury, occurred in one quarter of implanted patients. A recent open-label follow-up assessment of this study demonstrated a sustained benefit (35/16 mmHg reduction) over 22–53 months .
Although BAT targets a global suppression of sympathetic nerve activity, the importance of the kidneys in the control of arterial pressure with BAT was recently demonstrated. Lohmeier et al.[54▪▪] compared the effects of global and renal-specific suppression of sympathetic activity in dogs with obesity-induced hypertension. Both carotid baroreflex activation and bilateral renal denervation substantially decreased plasma renin activity and arterial pressure, suggesting that neurally induced renin secretion may be a major contributor in obesity hypertension. However, baroreflex activation also suppressed plasma norepinephrine concentration, tachycardia and glomerular hyperfiltration, while increasing fractional sodium excretion. This suggests that global suppression of sympathetic activity may confer additional benefits, beyond simply attenuating hypertension (Fig. 1).
Accumulating evidence indicates that the kidney is both a target and a contributor to sympathetic activation in hypertension and other sympathetically driven conditions. Although the mechanisms remain to be fully elucidated, recent animal studies suggests that RSNA, the renin–angiotensin system, and adipocyte-derived factors work in concert with one another in the development of hypertension. Particularly noteworthy are recent animal studies involving direct recordings of RSNA, which implicate a role of low-dose Ang II and obesity in the development of neurogenic hypertension. Although it remains unclear whether these mechanisms are consistent with the human condition, global and renal-specific targeted suppression of sympathetic activity has so far demonstrated favorable reductions in blood pressure in specific patient cohorts. Chronic BAT has also been shown to exert beneficial effects, but may carry greater risk of procedural complications. Interestingly, primarily uncontrolled data from renal denervation studies suggest potential positive effects on a number of comorbidities including sleep apnea, PCOS and insulin resistance, but long-term safety and efficacy data are lacking. Clearly, more research is needed to improve our understanding of the causative factors associated with human hypertension and to accurately describe the safety profile and therapeutic effects of new interventional approaches. Aside from their therapeutic usefulness, application of these techniques will further broaden our understanding of the neural control of kidney function and the mechanisms involved in the pathogenesis of neurogenic forms of hypertension.
M.S. is supported by a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) of Australia. R.L. is supported by an NHMRC of Australia Grant (ID: 586667).
This research was funded in part by grants from the National Health and Research Council of Australia (NHMRC) and the Victorian Government's Operational Infrastructure Support Program. M.S. is supported by a career fellowship from the NHMRC and is an investigator in studies sponsored by Medtronic and has received honoraria and lecture fees.
Conflicts of interest
There are no conflicts of interest.
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