Renal deafferentation: target for treatment of cardiovascular diseases involving sympathetic overactivity.

HIGH BLOOD PRESSURE associated with sympathetic overactivity is often associated with cardiovascular related mortality and/or morbidity. A therapeutic approach now considered for the treatment of resistant forms of the disease involves the selective denervation of the kidney (16, 51, 52, 57). Kidney function is known to be of primary importance in the long-term regulation and maintenance of arterial pressure (24). However, it is well documented that the autonomic nervous system also plays a critical role in the control of arterial pressure and in the pathogenesis of hypertension (1, 2, 36, 41), especially as it is able to modify renal function (19, 29). The autonomic nervous system and kidney are linked through renal nerves that are composed of both efferent sympathetic and afferent sensory fibers (19, 29). Although considerable evidence exists suggesting an overexcitation of the sympathetic nervous system in conjunction with neurohormonal factors in the pathogenesis of resistant forms of hypertension, these data do not unequivocally demonstrate whether the effects on arterial pressure following renal denervation are mediated by efferent renal sympathetic nerves or afferent sensory nerves originating in the kidney. This is especially true as afferent signals from the kidney alter the activity of preautonomic neurons in central sites involved in controlling arterial pressure and sympathetic nervous system activity (15), as clearly demonstrated in the article by Xu et al. (50), published in this issue of the American Journal of Physiology-Heart and Circulatory Physiology. Activation of efferent renal sympathetic nerves has been shown to increase renal vascular resistance, renin release, and water reabsorption and decrease sodium ion excretion (19, 29). Thus, as expected, denervation of efferent renal sympathetic nerves to the kidney results in reduced renin release and an increase in sodium excretion, but with little change in renal blood flow, perfusion pressure, and glomerular filtration rate (29). On the other hand, sensory nerves originating within the kidney carry information from renal chemoreceptors that detect changes in the composition of the interstitial fluid environment and renal mechanoreceptors which monitor hydrostatic pressure changes within the kidney (35, 39, 40, 47). Renal chemoreceptors have been classified as R1 and R2 by Recordati et al. (39, 40). R1 respond to renal ischemia, whereas R2 chemoreceptors are activated by both renal ischemia and changes in the ionic composition of the renal interstitium. R2 chemoreceptors do not respond to changes in arterial pressure but respond in an inverse relationship with a decrease in renal perfusion pressure. This latter group of chemoreceptors has also been suggested to function as renal osmoreceptors (39, 40). Furthermore, these renal chemoreceptors have been shown to be activated following intrarenal infusions of substance-P, bradykinin, and adenosine (27, 29–34). In addition, capsaicin, through activation of the nonselective cation channel transient receptor potential vanilloid 1 (32, 49), has been shown to activate renal chemoreceptors. Prostaglandin production has also been reported to activate these renal chemoreceptors, and inhibition of prostaglandin synthesis prevents the selective activation of R2 chemoreceptors (30). Finally, there are data suggesting that renal chemoreceptors also respond to cyclosporine A through a calcineurin-dependent process (56). Calcineurin inhibitors have been shown to enhance sympathetic neurotransmission by stimulating renal sensory nerve endings that contain synapsin-positive microvesicles (55). Renal mechanoreceptors monitor hydrostatic pressure changes in the kidney (35, 47) and at least two types of renal mechanoreceptors appear to exist: those with no spontaneous activity and those with tonic activity. However, both types of mechanoreceptors respond to increases in renal artery, venous, and/or pelvic pressure (35, 47). These renal receptors through their central connections are able to influence cardiovascular function not only by altering the release of vasopressin from the neurohypophysis (6, 11, 17, 18, 44) but also by increasing sympathetic nerve discharge to different vascular beds (7, 48) and the adrenal medulla (36) and through renorenal reflexes to alter kidney function (37, 38). Thus it is now accepted that afferent renal nerves and the central structures that integrate afferent renal nerve information may play an important role in the development and maintenance of hypertension (14, 15, 20, 22, 25, 28). Ciriello and colleagues were the first to identify central sites of integration of afferent renal nerve information (4, 7, 8, 10–14, 17, 18, 43, 45, 46). Specifically related to the recent article by Xu et al. (50) are the earlier findings that activation of afferent renal nerves in both the rat (11, 17, 18, 43, 45, 46) and cat (7, 8) evoked neuronal responses in the hypothalamic paraventricular nucleus (PVN). In earlier studies the output of vasopressin and oxytocin neurons to the posterior pituitary was primarily investigated (7, 11, 17, 18), as it had been reported that activation of afferent renal nerves resulted in the release of vasopressin into the circulation (6, 44). A study was also completed showing that direct PVN-spinal pathways that terminated within the intermediolateral cell column received afferent renal nerve inputs, suggesting a possible pathway by which afferent renal nerves could activate preganglionic neurons and arterial pressure (8). The study by Xu et al. (50) extends this line of investigation into central structures and pathways involved in integrating afferent renal nerve information and in the control of arterial pressure by examining the responses of PVN neurons that project directly to sympathoexcitatory sites within the rostral ventrolateral medulla (RVLM) to activation of afferent Address for reprint requests and other correspondence: J. Ciriello, Dept. of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Univ. of Western Ontario, London, ON, N6A5C1, Canada (e-mail: [email protected]). Am J Physiol Heart Circ Physiol 308: H970–H973, 2015; doi:10.1152/ajpheart.00148.2015. Editorial Focus