Hypertension is very common among patients with renal disease, and it has been attributed to a multitude of factors, but primarily to sodium retention, total body volume expansion, and increased activity of the renin-angiotensin system. Increasing evidence also suggests that afferent impulses from injured kidney may activate areas of the brain involved in the noradrenergic regulation of blood pressure and contribute to renal hypertension.
Our studies also provide evidence that down regulation of IL-1ß and nitric oxide, two modulators of central sympathetic nervous system (SNS) activity and blood pressure, may mediate central activation of the sympathetic nervous system in renal hypertension. Finally, our studies provide evidence that angiotensin II locally produced in the brain may mediate the down-regulation of IL-1ß and nNOS, and ultimately the rise in SNS activity and hypertension observed in hypertension associated with renal injury.
Hypertension is very common among patients with renal disease, and it can be either a cause or consequence of renal diseases.^1,2 Although hypertension associated with renal parenchymal disease constitutes approximately 5% of all hypertension, it becomes more prevalent as patients progress toward end-stage renal disease (ESRD). Blood pressure increases as renal function deteriorates. As a result, nearly all patients are hypertensive before requiring renal replacement therapy.
Regardless of the etiology of renal failure, approximately 85% of patients with ESRD have hypertension.³ Hypertension persists despite adequate dialysis regimen and multiple antihypertensive medications. Hypertension undoubtedly accelerates the decline in renal function and contributes to the progression of renal disease. Hypertension is the single most important predictor of coronary artery disease in ESRD patients, even more than cigarette smoking or hypertriglyceridemia,⁴ and treatment of hypertension in these patients is difficult and often inadequate. Such suboptimally controlled hypertension is in part responsible for the high incidence of cardiovascular events and deaths in ESRD patients. Understanding the mechanisms of hypertension in renal disease may lead to more appropriate forms of treatment.
The pathogenesis of hypertension in patients with renal disease and in those on maintenance dialysis is multifactorial, and may vary depending on the underlying renal disease (Table I). Traditionally, activation of the renin-angiotensin-aldosterone system and volume expansion secondary to sodium retention have been recognized as the most important factors.^5,6 However, clinical experience indicates that volume depletion and inhibition of the renin-angiotensin aldosterone system do not necessarily result in normalization of blood pressure. Many patients remain hypertensive despite reaching their true dry weights, and despite receiving maximal angiotensin II blockade. This suggests that other factors may play a role. The role of this manuscript is to review the evidence for a role of increased activity of the sympathetic nervous system.

Table 1. Factors implicated in the pathogenesis of hypertension in end-stage renal disease.

Sympathetic nervous system activity in chronic renal failure

Mounting evidence implicates increased SNS activity as the other major contributing factor to the pathogenesis of hypertension in patients with chronic renal failure (CRF). ^7-11 Sympathetic nervous stimulation augments cardiac output and increases peripheral resistance, and this works in concert with the renin-angiotensin-aldosterone system. ß-adrenergic stimulation promotes renin release, while angiotensin II stimulates the sympathetic nervous system (SNS). Plasma norepinephrine (NE) levels are usually increased in hemodialysis patients.^12,13 Direct recording of neuronal activity from postganglionic sympathetic fibers in the peroneal nerves of patients on chronic dialysis treatment have shown a greater rate of sympathetic nerve discharge than in control subjects.¹⁴ However, the cross-sectional nature of this patient-oriented research does not prove causality between the neurogenic signal from the failing kidney and the increased SNS activity.
Our studies on 5/6 nephrectomized (CRF) rats have provided the most convincing evidence yet for a role of the SNS in the pathogenesis of hypertension associated with CRF. The turnover rate ¹⁵ and the secretion of NE ¹⁶ from the posterior hypothalamic (PH) nuclei were greater in rats with 5/6 nephrectomy than in control rats. Bilateral dorsal rhizotomy prevented the development of hypertension and the increase in NE turnover in CRF rats.¹⁵
Moreover, microinjection of a neurotoxin, 6-hydroxy-dopamine, in the PH significantly reduced blood pressure (BP) in CRF rats.We postulated that the activation of these nuclei in the central nervous system results from impulses generating in the affected kidney and then transmitted to the central nervous system. This possibility is supported by multiple rationales. Studies in animals have shown that the kidney is a sensory organ richly innervated with baroreceptors and chemoreceptors.^17-19 Renal afferent nerves are connected directly or indirectly to a number of areas in the central nervous system that contribute to BP regulation.^20,21 Stimulation of renal receptors by adenosine, urea, or electrical impulses, evokes reflex increases in SNS activity and BP.^22-24
Renal afferent impulses may also play a role in the pathogenesis of hypertension in rats with experimentally induced CRF. In these animals, bilateral dorsal rhizotomy, at the level T-10 to L-3, prevented the increase in blood pressure and the progression of renal disease.²⁵ This suggests that increased renal sensory inputs from the injured kidney to the central nervous system may contribute to the development of hypertension and to the progression of renal disease in CRF rats. Activation of renal afferents appears also to be the primary mechanism for calcineurin inhibitor-induced hypertension in rats.^26,27 There is also some evidence that afferent impulses from injured kidneys may play an important role in activating SNS activity and raising BP in patients with kidney diseases. Converse et al ¹⁵ found that the rate of SNS discharge directly recorded from postganglionic sympathetic fibers in the peroneal nerves was greater in dialysis patients with their native kidneys than in those after bilateral nephrectomy. Ligtenberg et al reported an increase in muscle sympathetic nerve discharge in patients with chronic renal failure and renin-dependent hypertension, when compared with age- and weight-matched controls.²⁸ Klein et al ²⁹ have observed increased muscle sympathetic nerve activity in hypertensive patients with polycystic kidney disease regardless of kidney function.
These findings support the notion that increased afferent nervous inputs from kidneys with renal diseases may send signals to integrative sympathetic nucleiin the central nervous system and contribute to the pathogenesis of hypertension.The normalization of BP that follows bilateral nephrectomy may be largely due to elimination of these afferent impulses, rather than the removal of renin source.

Sympathetic nervous system activity in the phenol-renal injury model

Due to the extensive amount of scarring and decreased renal function, one cannot rule out the possibility of a contribution of renal insufficiency to the genesis of hypertension in the 5/6 nephrectomized rat model.
To this end, we have developed a new model of neurogenic hypertension in the rat, in which renal injury is not associated with any significant alteration of kidney function. Hypertension in this model is caused by injecting 50 µL of 10% phenol in the lower pole of one kidney. This leads to an immediate elevation of NE secretion from the PH, an increase in renal sympathetic nervous system activity (RSNA), and a rise in BP (Figure 1).³⁰ Renal denervation prevents the rise in NE secretion from the PH and the rise in BP caused by phenol injection. Serum creatinine did not change after the intrarenal administration of phenol, indicating that this model of hypertension does not cause any significant change in renal function.
The effects of the phenol-induced renal injury are long-lasting.³¹ We examined the chronic effects of an intrarenal injection of 50 µL of 10% phenol on BP and norepinephrine (NE) secretion from the PH. Systolic blood pressure remained elevated 4 weeks after receiving the intrarenal injection of phenol (from 128 ± 2.1 to 166 ± 4.0 mm Hg; P<0.01), but it did not change in rats that received the vehicle and in rats that were subjected to renal denervation. The secretion of NE from the PH was greater (P<0.01) in rats that received phenol than control and denervated rats. Ablation of the injured kidney led to normalization of BP and NE secretion from the PH in rats injected with phenol.These studies have demonstrated for the first time that a specific injury to a limited portion of one kidney (1 x 2 mm wide) in the rat may cause a permanent elevation of BP. Hypertension in this model is mediated by neurogenic mechanisms.

Nitric oxide and sympathetic nerve activity

Recent studies have provided convincing evidence that nitric oxide synthase (NOS) is present in specific areas of the brain and is involved in the nora-drenergic control of blood BP.^32,33 The neuronal isoform of NOS is an important component of transduction pathways that tonically inhibit sympathetic outflow from the brain stem.^34-36 In normal rats, the basal activity of the central SNS is regulated by local NO production.Administration of N^G-methyl-L-arginine to male Wistar rats increases RSNA and BP.³⁷ Evidence from our laboratory also indicates that local production of NO may modulate SNS activity in brain nuclei involved in the neurogenic regulation of BP. L-NAME, an inhibitor of NOS, increased BP and NE turnover rate in the brain of both control and CRF rats.³⁸
These studies are not in contradiction with the possibility that peripheral NO production may be reduced in CRF and contribute to elevation in BP.³⁹ In the phenol-renal injury model, we have shown that the abundance of nNOS in the PH, PVN, and LC was lower in rats that received phenol than in rats that received an intrarenal injection of saline.⁴⁰ This suggests that down-regulation of nNOS in the brain may mediate the activation of the SNS caused by intrarenal phenol.

The role of cytokines

Complex relationships exist between SNS activity, nitric oxide, and cytokines.^41-46 Several lines of evidence support the notion that interleukin 1ß (IL-1ß) may modulate central SNS activity. First, we have observed that the administration of ßL-1ß in the lateral ventricle of control and CRF rats lowers BP and NE secretion from the PH,⁴⁷ and increases the abundance of neuronal NOS mRNA in the PH, locus coeruleus (LC), and paraventricular nuclei (PVN). Second, infusion of a specific anti-rat IL-1ß antibody in the lateral ventricle led to an elevation in BP and in the secretion of NE from the PH of control rats, and to a further rise in BP and NE secretion from the PH of CRF rats. Third, the administration of an anti-rat IL-1ß antibody reduced the abundance of nNOS-mRNA in the PH, LC, and PVN of both control and CRF rats. In all, these findings suggest that IL-1ß modulates the activity of the sympathetic nervous system via activation of neuronal NOS.

Angiotensin-II and central SNS transmission in the phenol-renal injury model

We have studied the effects of losartan, a specific Ang II AT₁ receptor antagonist, on BP and SNS activity in the phenol-renal-injury model. Whether injected intravenously or in the lateral ventricle (ICV), losartan caused a significant (P<0.01) and dose-dependent inhibition of the effects of phenol on BP, NE secretion from the PH, and RSNA. Losartan also caused a significant (P<0.01) and dose-dependent rise in IL-1ß and nNOS-mRNA gene expression in the PH, PVN, and LC of phenol-injected rats.⁴⁸
These studies have demonstrated that the antihypertensive action of losartan in the phenol renal injury model is largely mediated by inhibition of central and peripheral SNS activity and suggest that activation of IL-1ß and nNOS, two important modulators of central SNS activity, mediate the inhibitory action of losartan on SNS activity.
These studies have also suggested that locally produced angiotensin II may be responsible for central activation of the SNS induced by phenol, and this action of angiotensin II may be mediated by downregulation of nNOS and IL-1ß.To further test this hypothesis, we studied the effect of an ICV infusion of angiotensin II on BP, NE secretion from the PH, RSNA, abundance of IL-1ß and nNOS mRNA in the PH, PVN, and LC of normal Sprague-Dawley rats. ICV infusion of Ang II raised BP, RSNA, and NE secretion from the PH compared with control rats. Ang II reduced the abundance of IL-1ß and nNOS mRNA in the PH, PVN, and LC. Pretreatment with losartan abolished the effects of Ang II on BP, RSNA and NE secretion from the PH and IL-1ß and nNOS mRNA.

Figure 1.
A. Levels of norepinephrine secretion from the posterior hypothalamic nuclei of Sprague-Dawley rats that received 50 µL of 10% phenol in the lower pole of one kidney (•), and those that received only vehicle (o).
B. B.Levels of mean arterial pressure in Sprague-Dawley rats that received 50 µL of 10% phenol in the lower pole of one kidney (•), and those that received only vehicle (o).
Each group comprised six rats. Values are expressed as means + SEM.

In all, these studies suggest that Ang II inhibits the expression of IL-1ß and nNOS in the brain. Since locally produced NO exerts a tonic inhibitory action on SNS activity, the decrease in NO expression caused by Ang II results in greater SNS activity and hypertension.These studies are also in keeping with our hypothesis that locally produced angiotensin II may mediate the central activation of the SNS observed in the phenol-renal-injury model.

Summary

Several factors have been implicated in the pathogenesis of hypertension associated with renal disease and/or renal failure. While the role of sodium retention, total body volume expansion, and increased activity of the reninangiotensin system are well recognized, increasing evidence suggests that afferent impulses from injured kidney may activate areas of the brain involved in the noradrenergic regulation of blood pressure and largely contribute to the development and maintenance of hypertension associated with renal diseases. Our studies also provide evidence for complex interactions between IL-1ß and nitric oxide in the regulation of central SNS activity and blood pressure. Following renal injury with phenol, the abundance of IL-1ß and nNOS in the brain decreases, and this may mediate the rise in SNS activity. Finally, our studies provide evidence that locally produced angiotensin II may ultimately mediate the downregulation of IL-1ß and nNOS in the brain resulting in increased SNS activity and hypertension in the phenol-renal injury model.

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