Reno-Cerebral Reflex Activates the Renin-Angiotensin System, Promoting Oxidative Stress and Renal Damage After Ischemia-Reperfusion Injury

Abstract

These data suggest that the renal and cerebral renin-angiotensin axes are interlinked by a reno-cerebral sympathetic reflex that is activated by ischemia-reperfusion, which contributes to ischemia-reperfusion-induced brain inflammation and worsening of the acute renal injury. Antioxid. Redox Signal. 27, 415-432.

The sympathetic nervous system in acute kidney injury

“…35 Spinal afferents innervating the kidneys elicit sympathoexcitatory and sympathoinhibitory reflexes, the latter are mainly via renal pelvic mechanosensory afferents while the former are due to activation of renal afferents localized within the renal parenchyma. 30 These data further support that sympathetic activation in response to acute IR is at least in part due to the activation of renal afferents and that an activated brain reninangiotensin system is involved. 25,26,36 Visceral spinal afferent neurons including nociceptors can be activated by substances released from damaged tissues (so called damage or danger-associated molecular patterns, DAMPs); 8 however, data demonstrating their GRISK participation in renal afferent and efferent nerve activation in acute renal IR are sparse.…”

“…26 Renal venous plasma noradrenaline concentrations obtained immediately after reperfusion of ischaemic kidneys were higher in male than in female rats, 27 suggesting sex-dependent differences in RSNA responses to renal ischaemia. 31 In apparent contrast to these findings, 30,31 recently published three-dimensional images of murine renal sympathetic nerves showed a significant reduction in sympathetic nerve fibre density on days 4 and 10 after bilateral clamping-induced IR in conjunction with an 80% reduction in renal noradrenaline content on post-ischaemic day 10 with incomplete renal sympathetic reinnervation by post-ischaemic day 28. RSNA, renal venous plasma noradrenaline concentrations and renal tyrosine hydroxylase expression have been shown to be elevated up to 24 hours after unilateral renal artery occlusion in rats and bilateral renal IR in mice.…”

“…25 A study in normoxic and chronically hypoxic female rats with two intact kidneys prior to occlusion reported a reduction in RSNA to the occluded kidney during unilateral renal artery occlusion accompanied by a rise in arterial pressure. 30 Another study in mice reported elevations in post-ischaemic renal noradrenaline contents up to day 16 after unilateral renal IR. The sex difference in post-ischaemic noradrenaline release in rats has been attributed to a sex dimorphism in renal monoaminooxidase activity, 28 which, however, cannot explain different responses of RSNA to renal ischaemia obtained from electrical multifibre recordings.…”

“…Sympathetic activation in renal IR may be due to excitatory reflexes elicited via renal sensory nerves and activation of certain brain areas ( Figure 1). 30,40 Furthermore, increased subfornical organ (SFO) expression of angiotensinogen and NADPH oxidase isoenzymes, Nox2 and Nox4, as well as increased tyrosine hydroxylase staining within the rostral ventrolateral medulla (RVLM) have been reported in mice 24 hours after renal IR. 35 Spinal afferents innervating the kidneys elicit sympathoexcitatory and sympathoinhibitory reflexes, the latter are mainly via renal pelvic mechanosensory afferents while the former are due to activation of renal afferents localized within the renal parenchyma.…”

“…A series of studies that applied renal nerve recordings showed that acute RSNA increases during renal artery occlusion can be prevented by centrally acting sympatholytic agents such as L-carnosine via a histamine H 3 receptor-dependent mechanism, 24 the α 2 -adrenoceptor/I 1 -imidazoline receptor agonists agmatine and moxonidine 33,34 as well as γamino-butyric acid. 30 The signs of brain inflammation and RVLM activation were abolished by intracerebroventricular (ICV) administration of the AT 1 receptor blocker losartan or the antioxidant tempol as well as by renal denervation or renal perivascular capsaicin administration to selectively lesion renal afferents. 10 During acute renal ischaemia, the activity of renal sensory nerves was found to be elevated.…”