The role of renal afferent signalling in chronic intermittent hypoxia-induced sympathoexcitation and hypertension

Introduction: Sensory inputs from the kidney induce sympatho-excitation, and are integrated in brainstem regions receiving protective sensory inputs from high- and low-pressure baroreceptors. Blunted baroreflex control of renal sympathetic nerve activity (RSNA) was revealed in hypertension models that involve renal inflammation. Suppression of inflammation restored the normal baroreflex control of RSNA in some of these models, suggesting that renal inflammation impairs baroreflex control of blood pressure through the disruption of renal afferent nerve signalling. Renal oxidative stress and inflammation are evident following exposure to chronic intermittent hypoxia (CIH) in addition to blunted baroreflex control of heart rate. However, little information is available about the baroreflex control of RSNA. In addition, because kidney injury disrupts renal afferent nerve signalling, changes in the renorenal reflex control of sympathetic outflow may occur following exposure to CIH. Therefore, understanding the stage at which baroreflexes and the reno-renal reflex are altered is required to explore the mechanisms that contribute to the early CIH-induced sympathetic hyperactivity and the onset of hypertension. Methods: Following exposure to CIH or normoxia, baroreflexes were examined under anaesthesia. Kidney excretory function was measured during the assessment of low-pressure baroreflex by volume expansion (VE). Baroreflexes were assessed before and after blockade of renal TRPV1 channels. Moreover, to investigate if the excitatory reno-renal reflex contributes to sympathetic over-activity in CIH, renal afferent nerves located in the renal pelvic wall were chemically stimulated by bradykinin and capsaicin, or inhibited by bradykinin receptor type 1 (BK1R) and/or 2 (BK2R) blockers, and cardiovascular and RSNA responses were measured. Renal histology, inflammation and oxidative stress biomarkers were assessed. Results: CIH-exposed rats were hypertensive with elevated RSNA, with no evidence of glomerular hypertrophy or renal inflammation and oxidative stress. Water and sodium excretion were increased following CIH exposure. However, diuresis and natriuresis during VE were attenuated in CIH-exposed rats despite preservation of the progressive decrease in RSNA during VE, suggesting that altered kidney excretory function in CIH was independent of neural control. The increase in atrial natriuretic peptide during VE was attenuated in CIH. Assessment of the high-pressure baroreflex revealed decreased slope in CIH-exposed rats with substantial hypertension, but not when hypertension was modest. Diuresis and natriuresis during VE were enhanced in CIH-exposed and sham rats following the intra-renal blockade of TPRV1 channels, suggesting a role for renal TRPV1 in the control of renal excretory function. However, TRPV1 protein expression in the kidney was unchanged and TRPV1 activation by intra-renal pelvic infusion of capsaicin induced a similar sympatho-excitation in sham and CIH-exposed rats. Moreover, sympatho-excitation during intra-renal pelvic infusion of bradykinin was suppressed in CIH-exposed rats. This was associated with 53% decreased expression of BK2R in the renal pelvic wall of CIH-exposed rats compared with sham rats. Inhibition of renal bradykinin receptors did not affect cardiovascular parameters or RSNA in sham and CIH-exposed rats. Conclusion: Our findings show no evidence of an excitatory reno-renal reflex driving sympathetic hyperactivity and the onset of hypertension in CIH. This was revealed by the absence of renal pathology despite the presence of a hypertensive phenotype. Moreover, the findings indicate suppressed rather than exacerbated sympatho-excitation in CIH-exposed rats in response to bradykinin. In addition, the baroreflex control of RSNA was maintained in CIHexposed rats with modest hypertension, indicating that blunted baroreflex control is not obligatory for the onset of hypertension in CIH. Overall, renal injury appears to develop after the progressive elevation of blood pressure, although it may also develop in circumstances of exposure to severe CIH, suggesting that chronic kidney disease, frequently observed concomitant with obstructive sleep apnoea (OSA), may be mitigated if OSA is controlled at an early stage

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

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

Chronic intermittent hypoxia impairs diuretic and natriuretic responses to volume expansion in rats with preserved low-pressure baroreflex control of the kidney

We examined the effects of exposure to chronic intermittent hypoxia (CIH) on baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory responses to volume expansion (VE) before and after intra-renal TRPV1 blockade by capsaizepine (CPZ). Male Wistar rats were exposed to 96 cycles of hypoxia per day for 14 days (CIH), or normoxia. Urine flow and absolute Na+ excretion during VE were less in CIH-exposed rats, but the progressive decrease in RSNA during VE was preserved. Assessment of the high-pressure baroreflex revealed an increase in the operating and response range of RSNA and decreased slope in CIH-exposed rats with substantial hypertension (+19mmHg basal mean arterial pressure, MAP), but not in a second cohort with modest hypertension (+12mmHg). Intra-renal CPZ caused diuresis, natriuresis and a reduction in MAP in sham and CIH-exposed rats. Following intra-renal CPZ, diuretic and natriuretic responses to VE in CIH-exposed rats were equivalent to sham. TPRV1 expression in the renal pelvic wall was similar in both experimental groups. Exposure to CIH did not elicit glomerular hypertrophy, renal inflammation or oxidative stress. We conclude that exposure to CIH: 1) does not impair the low-pressure baroreflex control of RSNA; 2) has modest effects on the high-pressure baroreflex control of RSNA, most likely indirectly due to hypertension; 3) can elicit hypertension in the absence of kidney injury; and 4) impairs diuretic and natriuretic responses to fluid overload. Our results suggest that exposure to CIH causes renal dysfunction, which may be relevant to obstructive sleep apnea

Effects of intracerebroventricular leptin and orexin-A on the baroreflex control of renal sympathetic nerve activity in conscious rats fed a normal or high-fat diet

This study examined the effect of leptin and orexin‐A on autonomic baroreflex control in conscious Wistar rats exposed to high‐fat (45% fat) or normal (3.4%) diet for 4 weeks. Renal sympathetic nerve activity (RSNA), mean arterial pressure (MAP) and heart rate (HR) were monitored during the generation of baroreflex gain curves and acute volume expansion (VEP). Intracerebroventricular (ICV) leptin (1 μg/min) increased RSNA in the normal diet group (0.31 ± 0.04 vs 0.23 ± 0.03 mV/s) and MAP in the high‐fat diet group (115 ± 5 vs 105 ± 5 mm Hg, P < .05). Orexin‐A (50 ng/min) increased RSNA, HR and MAP in the high‐fat diet group (0.26 ± 0.03 vs 0.22 ± 0.02 mV/s, 454 ± 8 vs 417 ± 12 beats/min, 117 ± 1 vs 108 ± 1 mm Hg) and the normal diet group (0.18 ± 0.05 vs 0.17 ± 0.05 mV/s, 465 ± 10 vs 426 ± 6 beats/min, 116 ± 2 vs 104 ± 3 mm Hg). Baroreflex sensitivity for RSNA was increased during ICV leptin by 50% in the normal diet group, compared to 14% in the high‐fat diet group (P < .05). Similarly, orexin‐A increased baroreflex sensitivity by 56% and 50% in the high‐fat and normal diet groups, respectively (all P < .05). During ICV saline, VEP decreased RSNA by 31 ± 5% (P < .05) after 10 minutes and the magnitude of this response was blunted during ICV infusion of leptin (17 ± 2%, P < .05) but not orexin‐A in the normal diet group. RSNA response to VEP was not changed during ICV leptin or orexin‐A in the high‐fat diet group. These findings indicate possible central roles for leptin and orexin‐A in modulating the baroreflexes under normal or increased fat intake in conscious rats and potential therapeutic approaches for obesity associated hypertension