Is Aberrant Reno-Renal Reflex Control of Blood Pressure a Contributor to Chronic Intermittent Hypoxia-Induced Hypertension?

Abstract

Renal sensory nerves are important in the regulation of body fluid and electrolyte homeostasis, and blood pressure. Activation of renal mechanoreceptor afferents triggers a negative feedback reno-renal reflex that leads to the inhibition of sympathetic nervous outflow. Conversely, activation of renal chemoreceptor afferents elicits reflex sympathoexcitation. Dysregulation of reno-renal reflexes by suppression of the inhibitory reflex and/or activation of the excitatory reflex impairs blood pressure control, predisposing to hypertension. Obstructive sleep apnoea syndrome (OSAS) is causally related to hypertension. Renal denervation in patients with OSAS or in experimental models of chronic intermittent hypoxia (CIH), a cardinal feature of OSAS due to recurrent apnoeas (pauses in breathing), results in a decrease in circulating norepinephrine levels and attenuation of hypertension. The mechanism of the beneficial effect of renal denervation on blood pressure control in models of CIH and OSAS is not fully understood, since renal denervation interrupts renal afferent signaling to the brain and sympathetic efferent signals to the kidneys. Herein, we consider the currently proposed mechanisms involved in the development of hypertension in CIH disease models with a focus on oxidative and inflammatory mediators in the kidneys and their potential influence on renal afferent control of blood pressure, with wider consideration of the evidence available from a variety of hypertension models. We draw focus to the potential contribution of aberrant renal afferent signaling in the development, maintenance and progression of high blood pressure, which may have relevance to CIH-induced hypertension.

Keywords: intermittent hypoxia; neurogenic hypertension; obstructive sleep apnoea syndrome; renal afferent nerves; reno-renal reflexes; sympathoexcitation.

Figure 1

A representation of possible pathways that enhance renal afferent nerve activity in a renal afferent nerve ending. B2, Bradykinin receptor type 2; PKC, protein kinase C; NE, norepinephrine; ET1, endothelin 1; ETA and ETB, endothelin receptor type A and type B; PKA, phosphokinase A; SP, substance P; CGRP, calcitonin gene related peptide; NK1, neurokinin receptor 1; TRPV1, Transient receptor potential cation channel; NMDA, N-methyl-D-aspartate receptors; ARNA, afferent renal nerve activity. Solid lines represent excitatory pathways and dashed lines represent inhibitory pathways. Chronic intermittent hypoxia may evoke aberrant renal afferent signaling contributing to hypertension through action on one or more of the above signaling mechanisms.

Figure 2

Mechanisms associated with the development of hypertension in chronic intermittent hypoxia (CIH)-exposed animals. Blue lines represent afferent signals; red lines represent efferent sympathetic discharge; yellow lines represent mechanisms involved in sensory long-term facilitation (sLTF). A decrease in the partial pressure of oxygen excites carotid body afferent discharge to the nucleus tractus solitarius (NTS). Signals are integrated to activate the rostral ventrolateral medulla (RVLM), increasing sympathetic nerve activity to different organs including the kidneys. An increase in efferent renal sympathetic nerve activity (ERSNA) activates the renin-angiotensin-aldosterone system (RAAS) and increases oxygen demand of the kidney. CIH also exerts direct and lasting effects on the kidneys. This stimulates afferent renal nerve signals, which are integrated in the NTS ultimately activating RVLM neurons, driving a reflex increase in ERSNA and additional release of angiotensin II (Ang II). Ang II causes vasoconstriction, which further decreases oxygen supply to the carotid bodies exaggerating their activity. Ang II stimulates circumventricular organs (CVO) such as the subfornical organ (SFO), which activates the paraventricular nucleus (PVN) of the hypothalamus enhancing sympathetic nerve activity. A decrease in renal oxygen levels is associated with increased secretion of erythropoietin. CIH elaborates a vicious cycle causing oxidative stress and inflammation in the carotid bodies, kidneys, and brain.