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Possible Protective Effect Or Harmful of Ketamine on Isquemia-Induced Acute Kidney Injury in a Pediatric Murine Model

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Possible Protective Effect Or Harmful of Ketamine on Isquemia-Induced Acute Kidney Injury in a Pediatric Murine Model Open Access Austin Journal of Anesthesia and Analgesia Special Article - Pediatric Anesthesiology Possible Protective Effect or Harmful of Ketamine on Isquemia-Induced Acute Kidney Injury in a Pediatric Murine Model Acosta-Murillo NR and Dueñas Gómez Z* Department of Physiological Sciences, National Abstract University of Colombia, Colombia The association between Ketamine and renal function begins in animal *Corresponding author: Dueñas Gómez Z, models, since the 1970s, particularly in relation to the effects on renal blood Department of Physiological Sciences, Division of flow [1,2]. Factors on renal hemodynamics such as decreased cardiac output Physiology, National University of Colombia, Bogotá, and blood pressure, sympathetic nerve stimulation and catecholamine release Colombia and, increased renin, angiotensin and vasopressin were involved [3]. From this century, the presence of N-Methyl-D-Aspartate Receptors (NMDA-R) outside Received: April 26, 2016; Accepted: June 01, 2016; the Central Nervous System (CNS) [4] where they had been initially identified Published: June 06, 2016 has been proposed, whereby the existence of the NMDA-R in the kidney and its functional role becomes important [5,6] in this way, the possible effects of NMDA-R antagonists, such as ketamine. Keywords: L-Glutamate; NMDA receptors; Renal function, Ketamine; Acute kidney injury; Ischemia/Reperfusion Abbreviations Α-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid (AMPA) receptor [8,9]. NMDA-R is large heterotetrameric membrane protein L-Glu: L-Glutamate; NMDA-R: N-Methyl-D-Aspartate complexes with a high permeability to calcium, which triggers a series Receptors; iGluRs: Ionotropic Glutamate Receptors; mGluRs: of calcium mediated intracellular events that have an outstanding Metabotropic Glutamate Receptors; AMPA: Α-Amino-3-Hydroxy- role in many physiological and pathological processes. Over the 5-Methyl-4-Isoxazolepropionic Acid, Gly: Glycine; IMCD: Inner past decade, a variety of NMDA-R subunits have been recognized: Medullary Collecting Duct, APV: D-Amino phosphono valeric Acid; the ubiquitously expressed NR1 subunit; a family of four distinct 7CK: 7-Chlorokynurenic Acid; Con: Conantokins-G and –T; PCP: NR2 subunits (A,B,C & D); and two NR3 subunits (A & B) [5]. Phencyclidine; PICU: Pediatric Intensive Care Unit; EPC: Epithelial These subunits have different isoforms and several splicing variants, Phenotypic Changes; AJC: Apical Junctional Complex; RBF: Renal of which the most studied are the NR1subunit, while the functional Blood Flow; AKI: Acute Kidney Injury; IRI: Ischemia-Reperfusion relevance of the different splicing forms of the NR2 and NR3 subunits Injury; MPO: Myeloperoxidase; LPS: lipopolysaccharide; TLR4: Toll- remains uncertain [5,7]. All NMDA receptors have NR1subunit; most Like Receptor; IL: Interleukin of them have a combination of NR2 and NR3 subunits. Activation of Introduction NMDA-R requires simultaneous binding of two different agonists, the L-Glu and Glycine (Gly), for this reason they are referred to as L-Glutamate (L-Glu) it is an α-amino acid abundant in the human co-agonists NMDA-R [10]. body and is a key compound in cellular metabolism, particularly in the human brain, where it is the most prominent neurotransmitter, NMDA-R and its distribution outside the CNS have emerged the main excitatory neurotransmitter, and also the precursor as an interesting research topic in the past decade. Recent studies for GABA, the main inhibitory neurotransmitter. L-Glu is a key show that the NMDA-R expressed in a variety of tissues, where it intermediate in metabolic pathways related to energy production, play an important role in numerous processes (such as proliferation, nitrogen metabolism and responses to oxidative stress. L-Glu exerts apoptosis, cell adhesion, and migration, actin rearrangement, cell its effects by acting on a large number of ionotropic (iGluRs) and growth and differentiation and regulation of hormone secretion), metabotropic (mGluRs) receptors, according to the mechanism by and may play an important role as a potential therapeutic target which their activation gives rise to a postsynaptic current, either for kidney and cardiovascular diseases, as well as bone diseases [4]. directly through the formation of ion channel pore or indirectly via NR1, the main subunit of the NMDA receptor, is located in several activation of ion channels through signaling cascades that involves extra neuronal tissues, including the rat kidney and heart. There is protein G, respectively. Glutamate receptors are expressed mainly also some expression of the NR1 subunit in the lung, thymus, and in the central nervous system and are involved in a number of stomach, suggesting that the NMDA receptor may play a much wider neurological conditions [5,7]. role than previously speculated [11]. Of the many specific subtypes of iGluRs, N-Methyl-D-Aspartate The functional relevance of NMDA-R for normal kidney Receptors (NMDA-R) are part of the most important group of physiology is not well understood although have been most receptors, together with kainate receptor, delta receptor and extensively studied in podocytes. It is also quite likely that NMDA-R Austin J Anesthesia and Analgesia - Volume 4 Issue 1 - 2016 Citation: Acosta-Murillo NR and Dueñas Gómez Z. Possible Protective Effect or Harmful of Ketamine on ISSN : 2381-893X | www.austinpublishinggroup.com Isquemia-Induced Acute Kidney Injury in a Pediatric Murine Model. Austin J Anesthesia and Analgesia. 2016; Dueñas Gómez et al. © All rights are reserved 4(1): 1045. Dueñas Gómez Z Austin Publishing Group in other parts of the kidney have different properties. NMDA-R is Of the above medications, the most widely used is the ketamine, a expressed in the renal cortex and medulla, and appears to play a phencyclidine derived. In the 1950s, Parke-Davis industries developed role in the regulation of renal blood flow, glomerular filtration, CI-395 (Phencyclidine or N-1-Phenyl-Cyclohexylpiperidine and proximal tubule reabsorption and urine concentration within (PCP) chlorhydrate) and CI-400 (N-ethyl-1-phenylcyclohexamine medullary collecting ducts [12]. The NR1 and NR2C subunits are chlorhydrate), among cyclohexylamine drugs. In 1978 its production present in the rat renal cortex and medulla. stopped because of the severe psychodysleptic effects and its abusive use as a recreational drug. Further research in the 1960s led to the The other NR2 subunit proteins are not expressed in the kidney. synthesis and development of ketamine (CI-581, 2-phenyl-Ochloro- NR1 subunit protein increases during renal development and NR2C is 2-methylamino-cyclohexanone) [15]. The first clinical study in also present but in a non-significant amount. Immunohistochemistry humans was conducted in 1964, and the drug was introduced into studies reveal that the NR1 subunit is abundant in the apical region clinical use in 1970. In the central nervous system, ketamine has of the proximal tubule (S1-S3) [11] and in the basolateral surface affinity for various receptors. Unlike many other anesthetics, it of the proximal convoluted tubule [13]. Until recently, there was does not affect gamma-aminobutyric acid receptors at clinically no evidence for expression of NR3 subunits (NR3a&NR3b) in the relevant concentrations. The analgesic effects are mediated mainly kidney. NR3 is highly expressed in the neonate with expression levels through blockade of NMDA-R and possibly by enhancement of substantially decreasing shortly after birth. It is not, however, entirely descending inhibition in the spinal cord in chronic pain conditions absent in the adult: although NR3a decreases with age; there are [16]. Even though there are extensive research and descriptions of examples of sustained NR3a levels, for instance, in discrete regions of ketamine effects in the nervous system, few studies have evaluated the central nervous system including the amygdala, layer V pyramidal the physiological, pharmacological and toxic effects of ketamine in neurons, mesencephalic trigeminal neurons and retina [13]. tissues outside the CNS, despite the recognition of the presence of The importance of the NMDA receptors in the kidney and NMDA-R almost ubiquitously. its functional role has been of great interest as research area, The effects of ketamine, as a blocker NMDA-R in different although experimental data are scarce. The results of the study by tissues to the nervous system, have not been established in a pediatric Sproul and colleagues and their main finding are related with the murine model. In this study, we wanted to identify in three different expression of the NR3a subunit of the NMDA-R in the kidney. By age groups, if the renal ischemia-reperfusion injury (assessed by immunofluorescence, it was possible to determine that there was very serum creatinine and histopathologic findings) is related to the dose little expression of NR3a in the adult mouse renal cortex, but this was of ketamine used as an anesthetic. not the case, in the medullary/papillary region, where they detected a high level of expression of this protein. In addition, they were able Materials and Methods to show in Inner Medullary Collecting Ductcells (IMCD),that NR3a Animals protein was upregulated by hypoxia and, when the mice were on The study was approved by the Ethics Committee of our College water restriction, a condition that induce an elevated renal medullary of Medicine and the procedures were carried out according to the osmolality. Thus, the decreased of oxygen level and
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