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

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          Abstract

          <p id="d6547550e319"> <b> <i>Aims:</i> </b> 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. </p><p id="d6547550e327"> <b> <i>Results:</i> </b> 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 <i>p</i> &lt; 0.05). Ischemia-reperfusion-induced renal damage and dysfunction persisted after controlling blood pressure with hydralazine. </p><p id="d6547550e338"> <b> <i>Innovation:</i> </b> This study uncovered a novel reflex pathway between ischemic kidney and the brain that sustains renal oxidative stress and local RAS activation to promote ongoing renal damage. </p><p id="d6547550e346"> <b> <i>Conclusions:</i> </b> 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. <i>Antioxid. Redox Signal.</i> 27, 415–432. </p>

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          The intrarenal renin-angiotensin system: from physiology to the pathobiology of hypertension and kidney disease.

          Hiroyuki Kobori, Masaomi Nangaku, L. Gabriel Navar … (2007)
          In recent years, the focus of interest on the role of the renin-angiotensin system (RAS) in the pathophysiology of hypertension and organ injury has changed to a major emphasis on the role of the local RAS in specific tissues. In the kidney, all of the RAS components are present and intrarenal angiotensin II (Ang II) is formed by independent multiple mechanisms. Proximal tubular angiotensinogen, collecting duct renin, and tubular angiotensin II type 1 (AT1) receptors are positively augmented by intrarenal Ang II. In addition to the classic RAS pathways, prorenin receptors and chymase are also involved in local Ang II formation in the kidney. Moreover, circulating Ang II is actively internalized into proximal tubular cells by AT1 receptor-dependent mechanisms. Consequently, Ang II is compartmentalized in the renal interstitial fluid and the proximal tubular compartments with much higher concentrations than those existing in the circulation. Recent evidence has also revealed that inappropriate activation of the intrarenal RAS is an important contributor to the pathogenesis of hypertension and renal injury. Thus, it is necessary to understand the mechanisms responsible for independent regulation of the intrarenal RAS. In this review, we will briefly summarize our current understanding of independent regulation of the intrarenal RAS and discuss how inappropriate activation of this system contributes to the development and maintenance of hypertension and renal injury. We will also discuss the impact of antihypertensive agents in preventing the progressive increases in the intrarenal RAS during the development of hypertension and renal injury.
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            KIM-1-mediated phagocytosis reduces acute injury to the kidney.

            Li-Li Yang, Craig Brooks, SHENG-XIANG XIAO … (2015)
            Kidney injury molecule 1 (KIM-1, also known as TIM-1) is markedly upregulated in the proximal tubule after injury and is maladaptive when chronically expressed. Here, we determined that early in the injury process, however, KIM-1 expression is antiinflammatory due to its mediation of phagocytic processes in tubule cells. Using various models of acute kidney injury (AKI) and mice expressing mutant forms of KIM-1, we demonstrated a mucin domain-dependent protective effect of epithelial KIM-1 expression that involves downregulation of innate immunity. Deletion of the mucin domain markedly impaired KIM-1-mediated phagocytic function, resulting in increased proinflammatory cytokine production, decreased antiinflammatory growth factor secretion by proximal epithelial cells, and a subsequent increase in tissue macrophages. Mice expressing KIM-1Δmucin had greater functional impairment, inflammatory responses, and mortality in response to ischemia- and cisplatin-induced AKI. Compared with primary renal proximal tubule cells isolated from KIM-1Δmucin mice, those from WT mice had reduced proinflammatory cytokine secretion and impaired macrophage activation. The antiinflammatory effect of KIM-1 expression was due to the interaction of KIM-1 with p85 and subsequent PI3K-dependent downmodulation of NF-κB. Hence, KIM-1-mediated epithelial cell phagocytosis of apoptotic cells protects the kidney after acute injury by downregulating innate immunity and inflammation.
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              The distant organ effects of acute kidney injury.

              Thorsten E E Grams, Hamid Rabb (2012)
              Despite the availability of renal replacement therapy, acute kidney injury (AKI) is associated with high mortality and morbidity. In humans, it is difficult to determine whether AKI is a cause or consequence of excess morbidity. In animal models, however, it is increasingly clear that AKI induces distant organ dysfunction. Identified pathways include inflammatory cascades, apoptosis, the induction of remote oxidative stress, and differential molecular expression. Specifically, growing evidence implicates renal injury as an instigator and multiplier of pulmonary, cardiac, hepatic, and neurologic dysfunction. Accurate identification of these pathways will be critical in developing targeted therapies to improve outcomes in AKI. The purpose of this review is to summarize both clinical and preclinical studies of AKI and its role in distant organ injury.
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                Author and article information

                Journal
                Title: Antioxidants & Redox Signaling
                Abbreviated Title: Antioxidants & Redox Signaling
                Publisher: Mary Ann Liebert Inc
                ISSN (Print): 1523-0864
                ISSN (Electronic): 1557-7716
                Publication date Created: September 2017
                Publication date (Print): September 2017
                Volume: 27
                Issue: 7
                Pages: 415-432
                Affiliations
                [1 ]Division of Nephrology, Nanfang Hospital, Southern Medical University, State Key Laboratory of Organ Failure Research, National Clinical Research Center of Kidney Disease, Guangzhou, P.R. China.
                [2 ]Hypertension, Kidney and Vascular Research Center, Georgetown University, Washington, District of Columbia.
                Article
                DOI: 10.1089/ars.2016.6827
                PMC ID: 5549812
                PubMed ID: 28030955
                SO-VID: 9a9d5f8e-8084-4a46-bc84-532ef6ef30d1
                Copyright © © 2017
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