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

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AlMarabeh, Sara
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University College Cork
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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.
Reno-renal reflex , Intermittent hypoxia , Renal nerves , Sympathetic control
AlMarabeh, S. Y. A. R. 2021. The role of renal afferent signalling in chronic intermittent hypoxia-induced sympathoexcitation and hypertension. PhD Thesis, University College Cork.
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