Experimental Physiology

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1 Exp Physiol (2015) pp Symposium Report Symposium Report The crosstalk between the kidney and the central nervous system: the role of renal nerves in blood pressure regulation Erika E. Nishi, Cássia T. Bergamaschi and Ruy R. Campos Department of Physiology, Cardiovascular Division, Universidade Federal de São Paulo, São Paulo, Brazil Experimental Physiology New Findings 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. (Received 14 October 2014; accepted after revision 9 December 2014; first published online 12 December 2014) Corresponding author R. R. Campos: Cardiovascular Division, Department of Physiology, Universidade Federal de São Paulo Escola Paulista de Medicina, Rua Botucatú 862, CEP , São Paulo, SP, Brazil. ruy.camposjr@unifesp.br Introduction The kidneys are vital organs in the regulation of arterial pressure and body fluid composition. The sympathetic nervous system is one of several factors that may influence the efficiency of the renal regulation of blood pressure. Anatomical and physiological evidence has shown that sympathetic nerves innervate juxtaglomerular cells, renal tubules and vasculature (DiBona, 2005). Thus, in a manner that depends on the frequency of renal sympathetic nerve activity (rsna), renal nerves mediate increases in urinary sodium and water excretion by regulating the renal tubular water and sodium reabsorption throughout the nephron, changes in renal blood flow and glomerular filtration rate by regulating the constriction of renal vasculature, and changes in the activity of the renin angiotensin system by regulating DOI: /expphysiol

2 480 E. E. Nishi and others Exp Physiol (2015) pp the renin release from juxtaglomerular cells (DiBona, 2005). Moreover, a growing body of both anatomical and physiological evidence has shown that sensory afferent fibres also innervate the kidneys and carry signals from the renal environment to the autonomic central nuclei that regulate blood pressure (Solano-Flores et al. 1997; Ye et al. 1997; Ciriello & de Oliveira, 2002). Thus, in this review, we focus on the evidence indicating a 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 the homeostasis in the body. Additionally, whether renal or autonomic dysfunction is the predominant contributor to systemic hypertension is still debated (Esler et al. 2010; Navar, 2010). Despite the fact that these two territories are apparently contradictory, the possibility that they are synergic and act in parallel not only to trigger but also to maintain hypertension should be taken into consideration. Moreover, it is known that rsna potentially predicts mean arterial blood pressure (Burgess et al. 1997). Consdering that the mechanisms related to blood pressure control are complex and it is not mediated by a single unifying pathway, the involvement of renal nerves in cardiovascular pathological conditions is considered in this review, particularly in a model of renovascular hypertension. The crosstalk between the brain and the kidneys is discussed. Efferent signals from the CNS to the kidney Anatomical studies using the trans-synaptic retrograde transport of a pseudorabies virus revealed the locations of the neurons that affect the sympathetic outflow to the kidney. Five cell groups in the brainstem and hypothalamus, namely the medullary raphe nuclei, the rostral ventrolateral medulla (RVLM), the ventromedial medulla, the pontine A5 noradrenergic cell group and the paraventricular nucleus of the hypothalamus (PVN), innervate the sympathetic preganglionic neurons that mainly reside in the intermediolateral column of the spinal cord and synapse with renal postganglionic neurons (Schramm et al. 1993). Most sympathetic renal premotor neurons are located in the RVLM and the caudal pons; nearly half of these neurons in the RVLM and all of the A5 cell group neurons are catecholamine-synthesizing cells (Ding et al. 1993). Although the blockade of glutamate receptors in the RVLM does not affect the resting blood pressure in the normal state (Sved et al. 2002), in the hypertensive state, such as the renovascular model, the glutamatergic input to the RVLM is increased, and its blockade reduces blood pressure (Bergamaschi et al. 1995), thereby contributing to the increase in rsna (Cravo et al. 2009). The RVLM receives input from the PVN, which is another region involved in the regulation of renal function. It was demonstrated that disinhibition of the PVN decreased glomerular filtration rate, effective renal plasma flow, urine flow and urinary sodium excretion (Haselton & Vari, 1998). Bilateral renal denervation (5 7 days before the experiments) significantly reduced both the renal vasoconstriction and the antidiuresis and abolished the antinatriuresis induced by PVN stimulation (Haselton & Vari, 1998). Taken together, these data suggest that neurons in the cardiovascular nuclei modulate the renal haemodynamics mediated by renal nerves. Afferent signals from the kidney to the CNS In addition to the abundant renal efferent sympathetic innervation, afferent sensory fibres are also present in the kidney. Viral tracing studies revealed that the cell bodies of the afferent fibres are located in the dorsal root ganglion from T10 to L1 of the spinal cord (Weiss & Chowdhury, 1998). Moreover, there is evidence that 8% of the sensory fibres project monosynaptically to the brainstem (Wyss & Donovan, 1984). A combination of functional and immunostaining techniques showed that electrical stimulation of the renal afferents increased the labelling of the neuronal activity marker Fos in many cardiovascular brain regions, such as the organum vasculosum of the lamina terminalis, the subfornical organ, the median preoptic nucleus and the PVN in the forebrain and the nucleus tractus solitarii, RVLM and A5 noradrenergic cell group in the brainstem (Solano-Flores et al. 1997). Supporting the existence of these anatomical projections of renal afferents, a study showed that electrical stimulation of renal afferents increased neuronal activity in the hypothalamus and brainstem (Calaresu & Ciriello, 1981). Further electrophysiological evidence has shown that afferent signals from the kidney are integrated supraspinally. The effect of electrical stimulation of renal afferents on rsna is prevented by renal denervation or spinal cord transection at the C2 level but not by brainstem transection at the pontine medullary junction or by lesion of the nucleus tractus solitarii (Saeki et al. 1988). A later study by the same researchers suggested that barosensory neurons in the RVLM responded to electrical stimulation of the renal afferents (Terui et al. 1988). Moreover, the plasma oxytocin and vasopressin levels were increased (Caverson & Ciriello, 1987) and the vasopressinergic and oxytocinergic neurons in the PVN activated after electrical renal afferent stimulation (Ciriello, 1998). These data suggest that neurons in the RVLM and PVN are involved in the integration of afferent signalling from the kidneys. Hence, previous evidence showed that crosstalk between the CNS and the kidneys through renal afferent and efferent nerves is an important mechanism in the regulation of the cardiovascular system and renal function.

3 Exp Physiol (2015) pp Crosstalk between the kidney and the central nervous system 481 Based on these studies, Fig. 1 summarizes the possibilities for the integration of afferent and efferent signalling. Changes in the information from the brain to the kidney and from the kidney to the brain are likely to be an important issue in pathophysiological conditions such as hypertension. In hypertension, the sympathoexcitation to the kidney and the increased afferent activity from the kidneytothecnsappeartoberelevanttotheoutcome of disease. In fact, renal denervation has been used as a novel therapy for resistant hypertension in patients. The ablation of renal nerves was shown to produce a long-term reduction in blood pressure in resistant hypertensive patients (Krum et al. 2014); however, the underlying mechanisms are still unclear, and its efficiency in humans has recently been disputed (Bhatt et al. 2014). Nevertheless, animal studies have shown that renal sensory afferent and sympathetic efferent fibres contribute to cardiovascular dysfunction. Studies of the pathophysiological effects of the overactivity of renal afferent and efferent nerves represent an exciting field of investigation to reveal a more refined tool to target the renal nerve as a treatment for hypertension. Renal nerve activation in renovascular hypertension Experimental studies have demonstrated that surgical renal denervation delays or prevents the increase in blood pressure in several models of hypertension (Katholi, 1983). Vasopressin Oxytocin Afferent fibres Efferent fibres Na + reabsorption Renal blood flow Tubule Vessel MR C1R C2R DRG T10 L1 IML Renin release JC Sympathetic Ganglion T10 T13 Figure 1. Schematic representation of the potential integration of renal afferent and efferent fibres in the CNS and kidneys Renal mechanoreceptors (MR) and chemoreceptors (C1R and C2R) sense changes in the kidney and provide sensory information to the CNS (represented as blue fibres). First-order neurons are located in the dorsal root ganglion (DRG) and project to the dorsal horn of the spinal cord, where they synapse with the neurons that project to the cardiovascular nuclei involved in blood pressure regulation, such as the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), the nucleus tractus solitarii (NTS), the A5 noradrenergic cell group and the rostral ventrolateral medulla (RVLM). Sympathetic premotor neurons from the PVN, RVLM and NTS project to the intermediolateral cell column (IML) and synapse with preganglionic neurons. Within the sympathetic ganglion, these fibres synapse with renal postganglionic fibres that innervate renal tubules, vasculature and juxtaglomerular cells (JC).

482 E. E. Nishi and others Exp Physiol 100.5 (2015) pp 479 484 A plausible mechanism for this decrease in blood pressure is the disruption of renal efferent sympathetic fibres.

In the normal state, renal afferent sensory activity leads to a reflex decrease in sympathetic outflow, which is known as an inhibitory renorenal reflex (Kopp et al. 1984).

4 482 E. E. Nishi and others Exp Physiol (2015) pp A plausible mechanism for this decrease in blood pressure is the disruption of renal efferent sympathetic fibres. Nevertheless, the interference of renal afferent sensory fibres is also likely to be involved. In the normal state, renal afferent sensory activity leads to a reflex decrease in sympathetic outflow, which is known as an inhibitory renorenal reflex (Kopp et al. 1984). The renorenal reflex is impaired in hypertension, and an increase in renal afferent activity augments the sympathoexcitation to the kidney and aggravates hypertension (Kopp & Buckley-Bleiler, 1989). Renal ischaemia and injury are conditions that may cause afferent sensory activation. Selective denervation of renal afferents prevented the increase in noradrenaline secretion from the posterior hypothalamus and prevented the increase in blood pressure following phenol-induced renal injury in rats (Ye et al. 1997). Renal artery occlusion-induced renal ischaemia increased the firing rate and Fos labelling in neurons in the RVLM of normal rats (Ding et al. 2001). These data suggest that intrarenal changes are sensed by renal afferents, and this information appears to be integrated in the brain such that in pathological states, this information contributes to sympathoexcitation. The intermediate phase of the two-kidney, one-clip (2K1C) model of renovascular hypertension is characterized by increased sympathoexcitation to the ischaemic (Nishi et al. 2013) and contralateral kidneys (Zhu et al. 2009). Original recordings of the ischaemic and contralateral kidneys of 2K1C rats obtained in our laboratory are shown in Fig. 2. Our group showed that the increase in rsna is maintained by increased activation of angiotensin II type 1 receptors in the RVLM (de Oliveira-Sales et al. 2010). Moreover, desensitization of the renal afferents by an intrathecal infusion of capsaicin at the T10 T13 level attenuated the increase in blood pressure in the 2K1C rats (Ciriello & de Oliveira, 2002). These observations show that both afferent and efferent renal fibres contribute to hypertension in the 2K1C model. Interestingly, denervation of the ischaemic kidney, but not the contralateral kidney, reduced the blood pressure in the 2K1C rats (Katholi, 1983). Accordingly, the increase in renal pelvic pressure that stimulates mechanoreceptors did not produce an inhibitory renorenal reflex to the contralateral kidney (Kopp & Buckley-Bleiler, 1989). The denervation of the ischaemic kidney augmented the urinary sodium excretion in both the ipsilateral and the contralateral kidneys, indicating an excitatory reflex that alters the sympathetic outflow from the ischaemic to the contralateral kidney in 2K1C hypertension (Kopp & Buckley-Bleiler, 1989), as represented in Fig. 3; this result is opposite to the inhibitory reflex from a healthy kidney to the contralateral kidney. It is unclear whether the impairment of the renorenal reflex in 2K1C rats results from changes in the kidney or the CNS; however, it is likely that changes in the signals Excitatory reflex CNS Inhibitory reflex 0.8 2K1C Contralateral Renal sympathetic nerve activity Normotensive 2K1C Ischaemic Contralateral kidney Clipped renal artery Ischaemic kidney Volts s Figure 2. Representative traces of the electrophysiological recording of sympathetic nerve activity in the contralateral and ischaemic kidneys of a two-kidney, one-clip (2K1C) rat and in the healthy kidney of a normotensive rat Renal sympathetic nerve activity is increased in the ischaemic and contralateral kidneys of the renovascular hypertensive rat compared with the normotensive rat. Figure 3. Schematic representation of the renorenal reflex in renovascular hypertension Afferent activity from the contralateral kidney leads to an inhibitory renorenal reflex to the ischaemic kidney, as occurs in a normal kidney. In contrast, increased afferent activity from the ischaemic kidney leads to an excitatory reflex that augments the sympathetic outflow in the contralateral kidney, contributing to hypertension.

5 Exp Physiol (2015) pp Crosstalk between the kidney and the central nervous system 483 from the ischaemic kidney trigger a disproportionate augmentation of rsna in renovascular hypertension. Conclusion In this brief report, the plausible mechanisms by which renal denervation leads to reduction in hypertension are discussed. The understanding of such mechanisms will further the possibility to target new therapeutical strategies for the treatment of hypertension. Recently, a novel technique for controlling resistant hypertension by carotid body stimulation was developed and tested clinically. Interestingly, the association of carotid body stimulation with renal denervation induced a differential effect on renal function in obesity-induced hypertensive dogs. The electrical carotid sinus stimulation reduced renal hyperfiltration, while renal denervation increased glomerular filtration rate (Lohmeier et al. 2012). This raises the possibilitiy that different classes of afferents (renal receptors, chemoreceptors and baroreceptors) may trigger specific central pathways leading to changes in sympathetic outflow to the kidneys that control renal function and, consquently, arterial pressure. References Bergamaschi C, Campos RR, Schor N & Lopes OU (1995). Role of the rostral ventrolateral medulla in maintenance of blood pressure in rats with Goldblatt hypertension. Hypertension 26, Bhatt DL, Kandzari DE, O Neill WW, D Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL & Investigators SH (2014). A controlled trial of renal denervation for resistant hypertension. NEnglJMed370, Burgess DE, Hundley JC, Li SG, Randall DC & Brown DR (1997). Multifiber renal SNA recordings predict mean arterial blood pressure in unanesthetized rat. Am J Physiol Regul Integr Comp Physiol 273, R851 R857. Calaresu FR & Ciriello J (1981). Renal afferent nerves affect discharge rate of medullary and hypothalamic single units in the cat. JAutonNervSyst3, Caverson MM & Ciriello J (1987). Effect of stimulation of afferent renal nerves on plasma levels of vasopressin. Am J Physiol Regul Integr Comp Physiol 252, R801 R807. Ciriello J (1998). Afferent renal inputs to paraventricular nucleus vasopressin and oxytocin neurosecretory neurons. Am J Physiol Regul Integr Comp Physiol 275, R1745 R1754. Ciriello J & de Oliveira CV (2002). Renal afferents and hypertension. Curr Hypertens Rep 4, Cravo SL, Campos RR, Colombari E, Sato MA, Bergamaschi CM, Pedrino GR, Ferreira-Neto ML & Lopes OU (2009). Role of the medulla oblongata in normal and high arterial blood pressure regulation: the contribution of Escola Paulista de Medicina UNIFESP. An Acad Bras Cienc 81, de Oliveira-Sales EB, Nishi EE, Boim MA, Dolnikoff MS, Bergamaschi CT & Campos RR (2010). Upregulation of AT 1 R and inos in the rostral ventrolateral medulla (RVLM) is essential for the sympathetic hyperactivity and hypertension in the 2K-1C Wistar rat model. Am J Hypertens 23, DiBona GF (2005). Physiology in perspective: the wisdom of the body. Neural control of the kidney. Am J Physiol Regul Integr Comp Physiol 289, R633 R641. Ding ZQ, Li YW, Wesselingh SL & Blessing WW (1993). Transneuronal labelling of neurons in rabbit brain after injection of herpes simplex virus type 1 into the renal nerve. JAutonNervSyst42, Ding YF, Zhang XX, Shi GM & He RR (2001). Renal ischemia enhances electrical activity and Fos protein expression of the rostral ventrolateral medullary neurons in rats. Sheng Li Xue Bao 53, Esler M, Lambert E & Schlaich M (2010). Point: Chronic activation of the sympathetic nervous system is the dominant contributor to systemic hypertension. JAppl Physiol 109, ; discussion Haselton JR & Vari RC (1998). Neuronal cell bodies in paraventricular nucleus affect renal hemodynamics and excretion via the renal nerves. Am J Physiol Regul Integr Comp Physiol 275, R1334 R1342. Katholi RE (1983). Renal nerves in the pathogenesis of hypertension in experimental animals and humans. Am J Physiol Renal Physiol 245, F1 F14. Kopp UC & Buckley-Bleiler RL (1989). Impaired renorenal reflexes in two-kidney, one clip hypertensive rats. Hypertension 14, Kopp UC, Olson LA & DiBona GF (1984). Renorenal reflex responses to mechano- and chemoreceptor stimulation in the dog and rat. Am J Physiol Renal Physiol 246, F67 F77. Krum H, Schlaich MP, Sobotka PA, Böhm M, Mahfoud F, Rocha-Singh K, Katholi R & Esler MD (2014). Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 383, Lohmeier TE, Iliescu R, Liu B, Henegar JR, Maric-Bilkan C & Irwin ED (2012). Systemic and renal-specific sympathoinhibition in obesity hypertension. Hypertension 59, Navar LG (2010). Counterpoint: Activation of the intrarenal renin-angiotensin system is the dominant contributor to systemic hypertension. JApplPhysiol109, ; discussion Nishi EE, Bergamaschi CT, Oliveira-Sales EB, Simon KA & Campos RR (2013). Losartan reduces oxidative stress within the rostral ventrolateral medulla of rats with renovascular hypertension. Am J Hypertens 26, Saeki Y, Terui N & Kumada M (1988). Physiological characterization of the renal-sympathetic reflex in rabbits. Jpn J Physiol 38, Schramm LP, Strack AM, Platt KB & Loewy AD (1993). Peripheral and central pathways regulating the kidney: a study using pseudorabies virus. Brain Res 616,

6 484 E. E. Nishi and others Exp Physiol (2015) pp Solano-Flores LP, Rosas-Arellano MP & Ciriello J (1997). Fos induction in central structures after afferent renal nerve stimulation. Brain Res 753, Sved AF, Ito S & Yajima Y (2002). Role of excitatory amino acid inputs to the rostral ventrolateral medulla in cardiovascular regulation. Clin Exp Pharmacol Physiol 29, Terui N, Saeki Y & Kumada M (1988). Barosensory neurons in the rostral ventrolateral medulla mediate the renal-sympathetic reflex in rabbits. Clin Exp Hypertens A 10 Suppl 1, Weiss ML & Chowdhury SI (1998). The renal afferent pathways in the rat: a pseudorabies virus study. Brain Res 812, Wyss JM & Donovan MK (1984). A direct projection from the kidney to the brainstem. Brain Res 298, Ye S, Ozgur B & Campese VM (1997). Renal afferent impulses, the posterior hypothalamus, and hypertension in rats with chronic renal failure. Kidney Int 51, Zhu GQ, Xu Y, Zhou LM, Li YH, Fan LM, Wang W, Gao XY & Chen Q (2009). Enhanced cardiac sympathetic afferent reflex involved in sympathetic overactivity in renovascular hypertensive rats. Exp Physiol 94, Additional information Competing interests None declared. Funding The authors wish to acknowledge funding support from the São Paulo Research Foundation (FAPESP) and National Counsel of Technological and Scientific Development (CNPq).

Experimental Physiology

Experimental Physiology 496 Exp Physiol 100.5 (2015) pp 496 501 Symposium Report Symposium Report Mechanisms of renal sympathetic activation in renovascular hypertension Ruy R. Campos 1, Elizabeth Barbosa Oliveira-Sales 1,ErikaE.Nishi