Involvement of Renal Sympathetic Nerve Activation on the Progression of Ischemic Acute Kidney Injury in the Mouse

Abstract

Abstract. Renal ischemia produces renal sympathoexcitation that is responsible for the development of ischemic acute kidney injury. The present study examined changes in the sympathetic nerve function in mice. Ischemic acute kidney injury was induced by occlusion of both renal pedicles. Renal ischemia/reperfusion increased blood urea nitrogen and plasma creatinine and expression of tyrosine hydroxylase, a rate-limiting enzyme for the biosynthesis of noradrenaline, in the kidney. Renal immunoreactivity of tyrosine hydroxylase was observed along with vessel and tubular structure both in the sham-operated and the ischemic acute kidney injury mice. The prominent morphological change was that tyrosine hydroxylase immunoreactivity was observed in the glomeruli of the ischemic acute kidney injury mice, whereas there are almost no tyrosine hydroxylase immunoreactivity signals in the glomeruli of the sham-operated mice. This tyrosine hydroxylase immunoreactivity in the glomeruli is colocalized with synapsin I immunoreactivity in the ischemic acute kidney injury mice. Intraperitoneal pretreatment with DSP-4 (50 mg/kg) attenuated these changes induced by renal ischemia/reperfusion. These results suggest that morphological and functional changes of glomerulus adrenergic nerve terminal are involved in the pathophysiology of ischemia/reperfusion-induced ischemic acute kidney injury.

The sympathetic nervous system in acute kidney injury

“…23,24 Experiments performed in female rats uninephrectomized immediately before IR did not show significant changes in RSNA during renal ischaemia. 23,25,29 In mice subjected to bilateral renal IR, plasma and renal noradrenaline concentrations were reported to be higher than in controls up to post-ischaemic day 3 and returned to control values by post-ischaemic day 7. 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.…”

“…These interventions include generalized SNS inhibition by centrally acting sympatholytic agents administered intravenously (iv), intraperitoneally (ip) or ICV, 24,[33][34][35][42][43][44][45] ganglionic blockade, 23 α 2 -adrenoceptor blockade, 31,46 non-selective β-adrenoceptor blockade, 47 chemical sympathectomy 29 and local renal denervation prior to or immediately after IR. These interventions include generalized SNS inhibition by centrally acting sympatholytic agents administered intravenously (iv), intraperitoneally (ip) or ICV, 24,[33][34][35][42][43][44][45] ganglionic blockade, 23 α 2 -adrenoceptor blockade, 31,46 non-selective β-adrenoceptor blockade, 47 chemical sympathectomy 29 and local renal denervation prior to or immediately after IR.…”

“…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. 23,25,29 In mice subjected to bilateral renal IR, plasma and renal noradrenaline concentrations were reported to be higher than in controls up to post-ischaemic day 3 and returned to control values by post-ischaemic day 7. 30 Another study in mice reported elevations in post-ischaemic renal noradrenaline contents up to day 16 after unilateral renal IR.…”

“…The presence or absence of reno-renal reflexes for different durations prior to and during renal ischaemia may have | 3 of 10 GRISK contributed to heterogeneous observations on RSNA during renal ischaemia. [23][24][25][26] While the majority of available data support that SNS activity including RSNA is elevated in response to reperfusion of ischaemic kidneys, 23,25,[29][30][31] data on long-term (ie beyond 3 days post ischaemia) effects of IR on SNS activity and renal sympathetic innervation are sparse, controversial and therefore require further investigations. Sympathetic activation in renal IR may be due to excitatory reflexes elicited via renal sensory nerves and activation of certain brain areas ( Figure 1).…”

“…Many studies reported beneficial effects of sympathetic inhibition on renal structure and excretory function in experimental IR performed in rabbits, rats and mice. These interventions include generalized SNS inhibition by centrally acting sympatholytic agents administered intravenously (iv), intraperitoneally (ip) or ICV, 24,[33][34][35][42][43][44][45] ganglionic blockade, 23 α 2 -adrenoceptor blockade, 31,46 non-selective β-adrenoceptor blockade, 47 chemical sympathectomy 29 and local renal denervation prior to or immediately after IR. 23,30,31,48 In dogs, administration of a β 1 -adrenoceptor blocker was without beneficial effects in this setting.…”