Autonomic Regulation of Kidney Function

A potential role for the renal innervation was first described in 1859 by Claude Bernard, who observed an increase in urine flow following section of the greater splanchnic nerve, which included the renal nerves. Subsequent studies provided little further clarity, leading Homer Smith in 1951 to declare that the renal innervation had little or no significance in controlling kidney hemodynamic or excretory function. However, since the 1960s, there has been increased attention to how the renal nerves may contribute to the deranged control of blood pressure and heart function cardiovascular diseases. The efferent (sympathetic) nerves have neuroeffector junctions which provide close contact with all vascular and tubular elements of the kidney. Activation of the sympathetic nerves at the resistance vessels, that is, the interlobular arteries afferent and even arterioles, modulates both renal blood flow and glomerular filtration rate; at the juxtaglomerular granular cells, they cause renin release and subsequent angiotensin II generation, and at the tubules there is a neurally stimulated increase in epithelial cell sodium transport. Less is known of the role of the afferent nerves, which primarily innervate the renal pelvis, and to a lesser degree the cortex and medulla. Their role is uncertain but sensory information passing to the brain can influence renal efferent nerve activity, forming the basis of both inhibitory and excitatory reno-renal reflexes. Increasingly, it is perceived that in a range of cardiovascular diseases such as cardiac failure, chronic renal disease, and hypertension, there is an inappropriate sympatho-excitation related to alterations in afferent renal nerve activity, which exacerbates the disease progression. The importance of the renal innervation in these disease processes has been emphasized in clinical studies where renal denervation in humans has been found to reduce blood pressure in resistant hypertensive patients and to ameliorate the progression of cardiac and kidney diseases, diabetes, and obesity and hypertension. The importance of both systemic and renal inflammatory responses in activating the neurohumoral control of the kidney is a continuing source of investigation.

Neurogenic tachykinin mechanisms in experimental nephritis of rats

We demonstrated earlier that renal afferent pathways combine very likely “classical” neural signal transduction to the central nervous system and a substance P (SP)–dependent mechanism to control sympathetic activity. SP content of afferent sensory neurons is known to mediate neurogenic inflammation upon release. We tested the hypothesis that alterations in SP-dependent mechanisms of renal innervation contribute to experimental nephritis. Nephritis was induced by OX-7 antibodies in rats, 6 days later instrumented for recording of blood pressure (BP), heart rate (HR), drug administration, and intrarenal administration (IRA) of the TRPV1 agonist capsaicin to stimulate afferent renal nerve pathways containing SP and electrodes for renal sympathetic nerve activity (RSNA). The presence of the SP receptor NK-1 on renal immune cells was assessed by FACS. IRA capsaicin decreased RSNA from 62.4 ± 5.1 to 21.6 ± 1.5 mV s (*p < 0.05) in controls, a response impaired in nephritis. Suppressed RSNA transiently but completely recovered after systemic administration of a neurokinin 1 (NK1-R) blocker. NK-1 receptors occurred mainly on CD11+ dendritic cells (DCs). An enhanced frequency of CD11c+NK1R+ cell, NK-1 receptor+ macrophages, and DCs was assessed in nephritis. Administration of the NK-1R antagonist aprepitant during nephritis reduced CD11c+NK1R+ cells, macrophage infiltration, renal expression of chemokines, and markers of sclerosis. Hence, SP promoted renal inflammation by weakening sympathoinhibitory mechanisms, while at the same time, substance SP released intrarenally from afferent nerve fibers aggravated immunological processes i.e. by the recruitment of DCs.

Sympathetic Renal Innervation and Resistant Hypertension

Hypertension in chronic renal disease and renovascular disease is often resistant to therapy. Understanding the pathogenic mechanisms responsible for hypertension in these conditions may lead to improved and more targeted therapeutic interventions. Several factors have been implicated in the pathogenesis of hypertension associated with renal disease and/or renal failure. Although the role of sodium retention, total body volume expansion, and hyperactivity of the renin-angiotensin-aldosterone system (RAAS) are well recognized, increasing evidence suggests that afferent impulses from the injured kidney may increase sympathetic nervous system activity in areas of the brain involved in noradrenergic regulation of blood pressure and contribute to the development and maintenance of hypertension associated with kidney disease. Recognition of this important pathogenic factor suggests that antiadrenergic drugs should be an essential component to the management of hypertension in patients with kidney disease, particularly those who are resistant to other modalities of therapy.