Experimental Physiology

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1 Exp Physiol 99.2 (2014) pp Symposium Report The neural regulation of the kidney in hypertension and renal failure Edward J. Johns Department of Physiology, University College Cork, Cork, Republic of Ireland Experimental Physiology New Findings What is the topic of this review? Reports that bilateral renal denervation in resistant hypertensive patients results in a longlasting reduction in blood pressure raise the question of the underlying mechanisms involved and how they may be deranged in pathophysiological states of hypertension and renal failure. What advances does it highlight? The renal sensory afferent nerves and efferent sympathetic nerves work together to exert an important control over extracellular fluid volume, hence the level at which blood pressure is set. This article emphasizes that both the afferent and the efferent renal innervation may contribute to the neural dysregulation of the kidney that occurs in chronic renal disease and resistant hypertension. Autonomic control is central to cardiovascular homeostasis, and this is exerted not only at the level of the heart and blood vessels but also at the kidney. At the kidney, the sympathetic neural regulation of renin release and fluid reabsorption may influence fluid balance and, in the longer term, the level at which blood pressure is set. The role of the renal innervation in the regulation of blood pressure has received renewed attention over the past few years, following the reports that bilateral renal denervation of resistant hypertensive patients resulted in a marked reduction in blood pressure, which has been maintained for several years. Such has been the interest that this approach of renal denervation is being applied in other patient groups with diabetes, obesity and renal failure, with the hope that there may be a sustained reduction in blood pressure as well as the amelioration of some aspects of the metabolic syndrome. However, the factors that come into play to cause the rise in blood pressure in these patient groups, particularly the resistant hypertensive patients, are far from clear. Moreover, the mechanisms leading to the fall in blood pressure following renal denervation of resistant hypertensive patients currently elude our understanding and is therefore an area that requires much more investigation to enhance our insight. (Received 16 June 2013; accepted after revision 13 August 2013; first published online 16 August 2013) Corresponding author E. J. Johns: Department of Physiology, Western Gateway Building, University College Cork, Cork, Republic of Ireland. e.j.johns@ucc.ie The sympathetic innervation of the kidney The kidney has a very dense sympathetic innervation, with preganglionic fibres originating from spinal segments between T11 and L3 and with postganglionic fibres passing into the coeliac, mesenteric, aorticorenal and splanchnic ganglia (Johns et al. 2011). These postganglionic fibres enter the kidney, closely following the renal arterial vasculature and eventually providing a network of nerve fibres primarily innervating the cortex but extending into DOI: /expphysiol

2 290 E. J. Johns Exp Physiol 99.2 (2014) pp the medulla (Fig. 1). These fibres are typical sympathetic fibres in that they have varicosities at neuroeffector junctions as they traverse the vascular, renincontaining granular cells and tubular structures of the kidney. Activation of the renal sympathetic nerves will therefore cause a change in functionality in terms of renal haemodynamic, excretory and secretory function, but the way in which this happens is not obvious. It is now apparent that there is a progressive recruitment of the different functionalities. Thus, at very low rates of activity there is a prompt increase in renin secretion, a β-adrenoceptor-mediated effect (Johns & Singer, 1974), at slightly higher levels there is a concomitant increase in fluid reabsorption, and it is only at the highest level of sympathoexcitation that there is a reduction in renal haemodynamics. Both these latter effects are mediated via α-adrenoceptors (Johns et al. 2011). Whilst superficially this seems to be a complex interaction, at a functional level it means that normally, and in response to everyday activities (for example, taking in a meal containing a high content of sodium chloride), sympathetic control is exerted on renin release and fluid reabsorption to ensure that there is a smooth excretion of an appropriate proportion of the sodium load. It is only when there are acute threatening fight and flight situations requiring redistribution of blood that sympathetic activity increases to a level at which renal blood flow and glomerular filtration rate are reduced, but these are short-term responses that have little long-term impact on fluid balance. Renal sympathetic nerve activity is determined by sensory information arising from the cardiovascular, somatic and visceral systems as well as the higher cortical centres. This input is integrated by various nuclei within the hypothalamic and medullary areas of the brain (Malpas, 2010). Pressure reduction at the carotid sinuses reflexly increases renal sympathetic nerve activity, which can lead to a renal nerve-dependent antinatriuresis and antidiuresis and renin secretion. In contrast, activation of the cardiopulmonary receptors, either by mechanical stretch or with volume expansion (Buckley & Johns, 2011), can reduce renal sympathetic nerve activity, increase sodium excretion and decrease renin secretion. Activation of visceral mechano- and chemoreceptors in the gut, liver and splenic areas leads to sympathetically mediated decreases in renal blood flow (Hamza & Kaufman, 2004). Studies from my own laboratory have shown that stimulation of the somatic sensory system, to depolarize somatic receptors, increased renal sympathetic nerve activity, which was accompanied by a renal nerve-dependent antinatriuresis (Zhang et al. 1997). These relationships are illustrated in Fig. 2. Thus, in normal everyday activities for example, exercise, in postprandial states and in response to stress, each of these various systems is called into play to ensure that sodium balance and hence cardiovascular homeostasis is maintained. Figure 1. Schematic diagram of the ganglia giving rise to the postganglionic sympathetic fibres that innervate the granular renin-containing cells of the afferent arteriole, the vascular smooth muscle cells of the resistance vessels and the epithelial cells of the proximal and distal tubules and the thick ascending limb of the loop of Henle.

3 Exp Physiol 99.2 (2014) pp Renal nerves in pathophysiological states 291 Renal afferent nerves The afferent innervation of the kidney has been perplexing, in terms of both anatomy and function, and has to a great extent lacked investigation. It has only been through the persistent and enlightening research of Kopp and her co-workers that this area has seen advances. Viral tracing studies have revealed that there is a sensory innervation of the kidney, with fibres passing into the spinal cord primarily at T12 L3 and synaptic connections in laminae I and III V (Ciriello & Calaresu, 1983). Thereafter, they project to the nucleus tractus solitarii, rostral ventrolateral medulla and paraventricular nucleus (Solano-Flores et al. 1997). A large proportion of the renal afferent nerves are located in the pelvic area of the kidney (Kopp et al. 2004), but there is probably also a low density of nerve terminals existing throughout the cortex and medulla. There is now good evidence that within this pelvic area there is often close apposition of afferent and efferent sympathetic nerves, which is expressed as a functional interaction. Early neurophysiological studies (Moss, 1989) identified neuronal activity elicited by acute ischaemia and volume expansion, which gradually gave rise to the view that these responses reflected stimulation of separate types of nerves that could be classified into chemo- and mechanosensitive afferent nerves (Stella & Zanchetti, 1991). Later studies were focused on how more physiological stimuli, such as urinary flow rate (mechanoreceptors) and urinary electrolyte and osmotic concentration (chemoreceptors) within the renal pelvis mediated changes in sympathetic nerve activity and the subsequent renal functional responses. The outcome of these investigations was the concept of renorenal reflexes (Fig. 3). Thus, an increase in ureteral pressure, due to diuresis or blockage of the ureter, elicits an elevation in afferent renal nerve activity from the ipsilateral kidney that causes a decrease in renal sympathetic nerve activity to the contralateral kidney. The withdrawal of sympathetic tone from the contralateral kidney leads to an increased fluid excretion from that kidney. This forms the basis of the inhibitory renorenal reflex (Johns & Kopp, 2013) and represents a situation in which a balance of fluid excretion is achieved between the two kidneys. The transduction process at the sensory nerve ending, which contains calcitonin gene-related peptide and substance P, is complex and involves a number of Figure 2. Schematic diagram of the afferent nerve activity arising from the different systems of the body, which passes directly or indirectly into the major brainstem and medullary areas regulating sympathetic outflow, primarily the nucleus tractus solitarii (NTS) There is output to the nucleus ambiguus (NA) for parasympathetic regulation, but also via the caudal and rostral venterolateral medulla (CVLM and RVLM). The preganglionic fibres track down via the intermediolateral tracts of the spinal cord and, at the ganglia, give rise to the postganglionic fibres that pass to the kidney.

4 292 E. J. Johns Exp Physiol 99.2 (2014) pp signalling factors. An increase in pelvic wall pressure leads to bradykinin activation of B 2 receptors, which increase protein kinase isoform C, causing cyclooxygenase isoenzyme 2 to generate prostaglandin E 2,whichactson EP 4 receptors. There is a subsequent stimulation of adenyl cyclasewhich,viaa3-5 cyclic adenosine monophosphate/ protein kinase isoenzyme A pathway, results in the release of substance P, which depolarizes the afferent nerve ending, thereby increasing activity passing to the central nervous system. There is also evidence that an increase in angiotensin II levels, induced by feeding a diet low in sodium, depresses the prostaglandin E-mediated activation of adenyl cyclase (see Johns & Kopp, 2013), thereby resetting the sensitivity of the transduction mechanism. Excitatory renorenal reflexes have also been described (Stella & Zanchetti, 1991), in which activation of the afferent nerves of one kidney elicits an increase of efferent activity in the contralateral kidney, but knowledge in this area is fragmentary. Early studies in the dog (Katholi et al. 1983) demonstrated that infusion of adenosine into the renal artery elicited an increase in blood pressure and plasma noradrenaline, both of which were prevented by prior renal denervation. Brody and co-workers reported that infusion of bradykinin directly into the renal artery of rats increased blood pressure, which was dependent on an intact renal innervation and consistent with sympathetic activation (Smits & Brody, 1984). Our own recent studies demonstrated that intrarenal administration of bradykinin induced an activation of the renal afferent nerves, which led to a renal nerve-mediated antinatriuresis Figure 3. Schematic diagram of the renorenal reflexes An inhibitory renorenal reflex is one where an increase in ipsilateral afferent renal nerve activity (ARNA) elicits a reduction in efferent renal nerve activity (ERNA) to the contralateral kidney. An excitatory renorenal reflex is one where the increase in ARNA results in an increase in ERNA to the contralateral kidney. and antidiuresis in the contralateral kidney (Barry & Johns, 2011). There is a view that the route of administration of these compounds, which is directly into the renal artery, is such that it activates sensory receptors within the renal cortex that are responsible for this excitatory renorenal reflex. Renal nerves and hypertension The sympathetic nervous system is one of the key regulators of the heart and blood vessels in the maintenance of cardiovascular homeostasis. There was an early recognition that in essential hypertension in man there was an important neurogenic component that contributed to the elevation in blood pressure. One possible mechanism would be a vasoconstriction of peripheral resistance vessels, leading to an increase in cardiac output and an underlying sodium retention. Early experimental investigations were focused on the spontaneously hypertensive rat, in which there was also an activation of the sympathetic nervous system (Lundin et al. 1984). It was found that renal denervation slowed but did not abolish the development of hypertension, and a similar pattern was observed in other models of hypertension, the deoxycorticosterone acetate salt and Goldblatt hypertensive rats (Johns et al. 2011). Thus, there was some indication that the renal nerves were in part causal but not totally responsible for the chronic elevation in blood pressure. One of the technical limitations in these studies was that of reinnervation, which occurs within 2 weeks in the rat, and this could partly have explained the slowing but not abolition of the rise in blood pressure. The recent observation in patients with resistant hypertension that bilateral renal denervation caused a marked and sustained reduction in blood pressure for at least 2 years (Esler, 2011) is at first sight different from the observations in the rat, but it may be that reinnervation in man is a much slower process. Interestingly, Kopp and co-workers have shown that reinnervation of both efferent and afferent renal nerves takes place at virtually the same rate (Mulder et al. 2013). These observations stimulate speculation regarding the mechanisms underlying the role of the renal nerves in hypertension and whether the hypertension is due to increased renal sympathetic nerve traffic impinging on the kidney to cause fluid retention or whether it is an increase in afferent renal nerve traffic impacting on the central nervous system to increase sympathetic outflow, or both. Interestingly, Kopp et al. (2007) have shown that there is a close physical apposition of afferent and efferent nerves in the renal pelvis, while functionally there is a proportional relationship whereby an increase in efferent nerve traffic also increases afferent nerve traffic. This interaction can be reset to different degrees dependent on dietary sodium intake, with the sensitivity of the relationship being enhanced by a

5 Exp Physiol 99.2 (2014) pp Renal nerves in pathophysiological states 293 low-sodium diet and depressed by a high-sodium diet. Selective afferent versus efferent renal denervation is difficult to achieve, but it is clear that dorsal rhizotomy to achieve a sensory denervation of the kidney has a major impact on blood pressure control (Kopp et al. 2003). Thus, although blood pressure in rats on a low or normal dietary intake of sodium is within the control range, those subjected to a high-salt diet become hypertensive. Together, these findings point to the afferent renal innervation playing an important role in the longterm regulation of blood pressure. Role of the renal innervation in renal disease There has been increasing focus on overactivity of the sympathetic nervous system associated with renal disease and renal failure. Orth et al. (2001) reported that the increased blood pressure occurring with chronic renal disease was strongly linked to an excitation of the sympathetic nervous system. Further evidence for this was provided by Hausberg et al. (2002) in end-stage renal failure patients, by using micro-neurography to measure muscle sympathetic nerve activity, which showed that the bursting activity in the neurogram was some three times higher in the renal failure patients than in normal individuals (Fig. 4). Interestingly, in the renal failure patients if the diseased native kidneys were removed during transplantation surgery, it was subsequently found that the muscle sympathetic nerve bursting activity was no different from that of normal subjects. These findings were consistent with the view that the overactivity of the sympathetic nervous system was driven by a signal from the diseased kidney. This contention was supported by reports that catecholamine excretion was elevated in haemodialysis patients and in polycystic kidney disease (Klein et al. 2001). Campese et al. (2006) have reviewed the reasons underlying the difficulty in treating the hypertension associated with renal parenchymal disease and highlighted a role for the inappropriate stimulation of the sensory receptors within the kidney. This group used a rat model of renal injury, a localized small injection of phenol into the pole of the kidney, and demonstrated that this increased both afferent and efferent renal nerve activity together with a prolonged increase in blood pressure. The increased efferent sympathetic nerve activity did not occur if the injured kidney was subjected to prior denervation. Moreover, they reported that chronic renal failure in a rat model of 5/6th nephrectomy was associated with hypertension, which was prevented by bilateral dorsal rhizotomy. Recent studies from my laboratory have used a different model, that of the cisplatin-induced renal failure (Goulding & Johns, 2011). In this model, there is increased fractional noradrenaline excretion 1 week after induction of renal failure, which is associated with a blunted baroreceptor reflex regulation of renal sympathetic nerve activity and renal nerve-dependent excretion of a sodium load. Together, these studies highlight that the renal afferent nerves may be activated as a result of renal injury or in renal disease in a way to increase their activity which, within the central nervous system, leads to a sympathoexcitation, a blunting of the reflex neural control of the kidney and a dysregulation of cardiovascular control. These experimental studies therefore help to provide insight into the recent demonstration by Krum et al. (2009) that bilateral renal denervation in resistant hypertensive patients caused a prolonged reduction in blood pressure. The outcomes of these ongoing human investigations are severalfold. They show directly in man that the kidney can be a potent contributor to development of hypertension via signals passing through the renal nerves. The evidence to date suggests that in these patients some aspects of the high pressure may change the environment surrounding the sensory nerve endings within the kidney, which initiates an inappropriate activation of the afferent nerves. It may be the increased afferent nerve activity which elicits the sympathoexcitation and, at the kidney, leads to a neurally mediated retention of sodium, upsetting the regulation of extracellular fluid volume and ultimately contributing to the level at which blood pressure is set. References Figure 4. The bursting rate of muscle sympathetic nerve activity in end-stage renal failure patients before and after nephrectomy (Nephx) to remove the diseased native kidney. Barry EF & Johns EJ (2011). 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6 294 E. J. Johns Exp Physiol 99.2 (2014) pp Ciriello J & Calaresu FR (1983). Central projections of afferent renal fibers in the rat: an anterograde transport study of horseradish peroxidase. JAutonNervSyst8, Esler M (2011). The sympathetic nervous system through the ages: from Thomas Willis to resistant hypertension. Exp Physiol 96, Goulding N & Johns EJ (2011). The impact of cisplatin induced renal failure on baroreflex regulation of renal sympathetic nerve activity (RSNA) in the male Wistar rat. FASEB J 25, Hamza SM & Kaufman S (2004). Splenorenal reflex modulates renal blood flow in the rat. JPhysiol558, Hausberg M, Kosch M, Harmelink P, Barenbrock M, Hohage H, Kisters K, Dietl KH & Rahn KH (2002). Sympathetic nerve activity in end-stage renal disease. Circulation 106, Johns EJ & Kopp UC (2013). Neural control of renal function. In Seldin and Giebisch s The Kidney: Physiology and Pathophysiology, ed. Alpern R, Kaplan MJ & Moe OW, pp Elsevier, UK. Johns EJ, Kopp UC & DiBona GF (2011). Neural control of renal function. Compr Physiol 1, Johns EJ & Singer B. (1974). Comparison of the effects of propranolol and ICI in blocking the renin releasing effect of renal nerve stimulation in the cat. Br J Pharmacol 52, Katholi RE, Hageman GR, Whitlow PL & Woods WT (1983). Hemodynamic and afferent renal nerve responses to intrarenal adenosine in the dog. Hypertension 5, I149 I154. Klein IH, Ligtenberg G, Oey PL, Koomans HA & Blankestijn PJ (2001). Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. JAmSoc Nephrol 12, Kopp UC, Cicha MZ, Nakamura K, Nusing RM, Smith LA & Hökfelt T (2004). Activation of EP4 receptors contributes to prostaglandin E 2 -mediated stimulation of renal sensory nerves. Am J Physiol Renal Physiol 287, F1269 F1282. Kopp UC, Cicha MZ & Smith LA (2003). Dietary sodium loading increases arterial pressure in afferent renal-denervated rats. Hypertension 42, Kopp UC, Cicha MZ, Smith LA, Mulder J & Hökfelt T (2007). Renal sympathetic nerve activity modulates afferent renal nerve activity by PGE 2 -dependent activation of α 1 -and α 2 -adrenoceptors on renal sensory nerve fibers. Am J Physiol Regul Integr Comp Physiol 293, R1561 R1572. Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT & Esler M (2009). Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 373, Lundin S, Ricksten SE & Thorén P (1984). Renal sympathetic activity in spontaneously hypertensive rats and normotensive controls, as studied by three different methods. Acta Physiol Scand 120, Malpas SC (2010). Sympathetic nervous system overactivity and its role in the development of cardiovascular disease. Physiol Rev 90, Moss NG (1989). Electrophysiological characteristics of renal sensory receptors and afferent renal nerves. Miner Electrolyte Metab 15, Mulder J, Hökfelt T, Knuepfer MM & Kopp UC (2013). Renal sensory and sympathetic nerves reinnervate the kidney in a similar time-dependent fashion after renal denervation in rats. Am J Physiol Regul Integr Comp Physiol 304, R675 R682. Orth SR, Amann K, Strojek K & Ritz E (2001). Sympathetic overactivity and arterial hypertension in renal failure. Nephrol Dial Transplant 16(Suppl 1), Smits JF & Brody MJ (1984). Activation of afferent renal nerves by intrarenal bradykinin in conscious rats. Am J Physiol Regul Integr Comp Physiol 247, R1003 R1008. Solano-Flores LP, Rosas-Arellano MP & Ciriello J (1997). Fos induction in central structures after afferent renal nerve stimulation. Brain Res 753, Stella A & Zanchetti A (1991). Functional role of renal afferents. Physiol Rev 71, Zhang T, Huang C & Johns EJ (1997). Neural regulation of kidney function by the somatosensory system in normotensive and hypertensive rats. Am J Physiol Regul Integr Comp Physiol 273, R1749 R1757. Additional information Competing interests None declared. Funding The author wishes to acknowledge funding support from the following organizations: British Heart Foundation; Health Research Board, Science Foundation Ireland; Irish Research Council for Science, Engineering and Technology; the Medical School, Birmingham; The School of Medicine, University College Cork; and the Wellcome Trust.