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

ABSTRACT: A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury.Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, renin-angiotensin system (RAS), increased sympathetic activity in the kidney and the cerebral sympathetic regulatory regions, and induced brain inflammation and kidney injury. Selective renal afferent denervation with capsaicin or renal denervation significantly attenuated IRI-induced activation of central RAS and brain inflammation. Central blockade of RAS or oxidative stress by intracerebroventricular (ICV) losartan or tempol reduced the renal ischemic injury score by 65% or 58%, respectively, and selective renal afferent denervation or reduction of sympathetic tone by ICV clonidine decreased the score by 42% or 52%, respectively (all p?

SUBMITTER: Cao W

PROVIDER: S-EPMC5549812 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Cao Wei W Li Aiqing A Li Jiawen J Wu Chunyi C Cui Shuang S Zhou Zhanmei Z Liu Youhua Y Wilcox Christopher S CS Hou Fan Fan FF

Antioxidants & redox signaling 20170131 7

<h4>Aims</h4>A kidney-brain interaction has been described in acute kidney injury, but the mechanisms are uncertain. Since we recently described a reno-cerebral reflex, we tested the hypothesis that renal ischemia-reperfusion injury (IRI) activates a sympathetic reflex that interlinks the renal and cerebral renin-angiotensin axis to promote oxidative stress and progression of the injury.<h4>Results</h4>Bilateral ischemia-reperfusion activated the intrarenal and cerebral, but not the circulating, ...[more]

PMID: 28030955

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Project description:BackgroundNOD-like receptors (NLR) are intracellular sensors of the innate immune system, with the NLRP3 being a pro-inflammatory member that modulates cardiac ischemia-reperfusion injury (IRI) and metabolism. No information is available on a possible role of anti-inflammatory NLRs on IRI and metabolism in the intact heart. Here we hypothesize that the constitutively expressed, anti-inflammatory mitochondrial NLRX1, affects IRI and metabolism of the isolated mouse heart.MethodsIsolated C57Bl/6J and NLRX1 knock-out (KO) mouse hearts were perfused with a physiological mixture of the essential substrates (lactate, glucose, pyruvate, fatty acid, glutamine) and insulin. For the IRI studies, hearts were subjected to either mild (20 min) or severe (35 min) ischemia and IRI was determined at 60 min reperfusion. Inflammatory mediators (IL-6, TNFα) and survival pathways (mito-HKII, p-Akt, p-AMPK, p-STAT3) were analyzed at 5 min of reperfusion. For the metabolism studies, hearts were perfused for 35 min with either 5.5 mM 13C-glucose or 0.4 mM 13C-palmitate under normoxic conditions, followed by LC-MS analysis and integrated, stepwise, mass-isotopomeric flux analysis (MIMOSA).ResultsNLRX1 KO significantly increased IRI (infarct size from 63% to 73%, end-diastolic pressure from 59 mmHg to 75 mmHg, and rate-pressure-product recovery from 15% to 6%), following severe, but not mild, ischemia. The increased IRI in NLRX1 KO hearts was associated with depressed Akt signaling at early reperfusion; other survival pathways or inflammatory parameters were not affected. Metabolically, NLRX1 KO hearts displayed increased lactate production and glucose oxidation relative to fatty acid oxidation, associated with increased pyruvate dehydrogenase flux and 10% higher cardiac oxygen consumption.ConclusionDeletion of the mitochondrially-located NOD-like sensor NLRX1 exacerbates severe cardiac IR injury, possibly through impaired Akt signaling, and increases cardiac glucose metabolism.

Project description:Renin-angiotensin-aldosterone system (RAAS) plays an important role in the regulation of blood pressure and brain function. Therefore, we studied the dynamic changes in the RAAS in the blood, cerebral cortex, and hippocampus and the effects of RAAS inhibitors on spatial learning and memory and hippocampal apoptosis in a rat model of chronic cerebral ischemia (CCI) established by bilateral ligation of the common carotid arteries of rats. The levels of renin, angiotensin II (Ang II), and aldosterone (ALD) in the plasma, and the homogenates of the left side of cerebral cortex and whole hippocampus of rats were detected on day 1, 3, 7, 14, 21, and 30 by radioimmunoassay. Spatial learning and memory and hippocampal apoptosis were evaluated on day 30 by Morris water maze test (navigation and space exploration tests) and terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay, respectively, after rats were orally administered with distilled water (DW), renin inhibitor aliskiren (30 mg/kg), Ang converting enzyme inhibitor enalapril (4 mg/kg), or Ang II receptor antagonist candesartan (2 mg/kg) daily for 30 days. The results showed that the levels of renin and Ang II were significantly higher but ALD fluctuated in the blood, cerebral cortex, and hippocampus in CCI rats compared to normal rats. However, aliskiren and enalapril could significantly decrease (p < 0.05) the levels of renin, Ang II and ALD in the blood, cerebral cortex, and hippocampus compared to DW treatment; while candesartan had similar effect on renin and ALD but no effect on Ang II in CCI rats. Furthermore, spatial learning and memory were significantly decreased but apoptosis in the hippocampus was obviously increased in CCI rats compared to normal rats (p < 0.05). However, aliskiren, enalapril, and candesartan were equally effective to improve spatial learning and memory and decrease apoptosis in the hippocampus. Therefore, RAAS plays an important role in the development of cerebral ischemia and RAAS inhibitors aliskiren, enalapril, and candesartan improve spatial learning and memory and protect brain injury by inhibiting hippocampal apoptosis in CCI rats.

Dataset Information

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

Publications

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

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