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Impaired Renal Organic Anion Transport 1 (SLC22A6) and Its Regulation Following Acute Myocardial Infarction and Reperfusion Injury in Rats T

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Impaired Renal Organic Anion Transport 1 (SLC22A6) and Its Regulation Following Acute Myocardial Infarction and Reperfusion Injury in Rats T BBA - Molecular Basis of Disease 1865 (2019) 2342–2355 Contents lists available at ScienceDirect BBA - Molecular Basis of Disease journal homepage: www.elsevier.com/locate/bbadis Impaired renal organic anion transport 1 (SLC22A6) and its regulation following acute myocardial infarction and reperfusion injury in rats T Kungsadal Sirijariyawata, Atcharaporn Ontawonga,b, Siripong Paleec, Savitree Thummasornc, Chayodom Maneechotec, Oranit Boonphanga, Varanuj Chatsudthipongd, Nipon Chattipakorna,c, ⁎ Chutima Srimaroenga, a Department of Physiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand b Division of Physiology, School of Medical Sciences, University of Phayao, Phayao, Thailand c Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand d Research Center of Transport Protein for Medical Innovation, Faculty of Science, Mahidol University, Bangkok, Thailand ARTICLE INFO ABSTRACT Keywords: Acute kidney injury (AKI) is a high frequent and common complication following acute myocardial infarction Organic anion transporter 1 (AMI). This study examined and identified the effect of AMI-induced AKI on organic anion transporter 1 (Oat1) Organic anion transporter 3 and Oat3 transport using clinical setting of pre-renal AKI in vivo. Cardiac ischaemia (CI) and cardiac ischaemia Acute kidney injury and reperfusion (CIR) were induced in rats by 30-min left anterior descending coronary artery occlusion and 30- Acute myocardial ischemia and reperfusion min occlusion followed by 120-min reperfusion, respectively. Renal hemodynamic parameters, mitochondrial Mitochondrial dysfunction function and Oat1/Oat3 expression and function were determined along with biochemical markers. Results Oxidative stress showed that CI markedly reduced renal blood flow and pressure by approximately 40%, while these parameters were recovered during reperfusion. CI and CIR progressively attenuated renal function and induced oxidative stress by increasing plasma BUN, creatinine and malondialdehyde levels. Correspondingly, SOD, GPx, CAT mRNAs were decreased, while TNFα, IL1β, COX2, iNOS, NOX2, NOX4, and xanthine oxidase were increased. Mitochondrial dysfunction as indicated by increasing ROS, membrane depolarisation, swelling and caspase3 activation were shown. Early significant detection of AKI; KIM1, IL18, was found. All of which deteriorated para- aminohippurate transport by down-regulating Oat1 during sudden ischaemia. This consequent blunted the trafficking rate of Oat1/Oat3 transport via down-regulating PKCζ/Akt and up-regulating PKCα/NFκB during CI and CIR. Thus, this promising study indicates that CI and CIR abruptly impaired renal Oat1 and regulatory proteins of Oat1/Oat3, which supports dysregulation of remote sensing and signalling and inter-organ/orga- nismal communication. Oat1, therefore, could potentially worsen AKI and might be a potential therapeutic target for early reversal of such injury. 1. Introduction strategies leading to rising in-hospital mortality. Previous studies de- monstrate that cardiac and renal ischaemia and reperfusion (I/R) share Acute kidney injury (AKI) is frequently associated and defined to be common pathophysiological mechanisms causing severe cellular in- a common complication following acute myocardial infarction (AMI) juries, which lead to organ dysfunctions and are believed to be multi- due to transient episodes of ischaemia (hypoperfusion) and reperfusion factorial [2]. During renal I/R condition, the reperfusion itself causes [1]. At present, the prevalence of AKI after AMI remains high with a severe cellular injury leading to AKI and renal dysfunction [3]. Renal broad range of 5–59%, depending upon AKI definition and clinical hemodynamic alteration, nitric oxide production, inflammation and characteristics [1,2], which persist due to failure of preventive oxidative stress have been proposed to play as major mediators of Abbreviations: Oat1, organic anion transporter 1; Oat3, organic anion transporter 3; CI, cardiac ischaemia; CIR, cardiac ischaemia and reperfusion; SOD, superoxide dismutase; GPx, glutathione peroxidase; CAT, catalase; TNFα, tumour necrosis factor alpha; IL1β, interleukin 1 beta; COX2, cyclooxygenase 2; iNOS, inducible nitric oxide; NOX2, NAPDH oxidase2; NOX4, NAPDH oxidase4; KIM1, kidney injury molecule 1; IL18, interleukin 18; PKCζ, protein kinase zeta; Akt, protein kinase B; PKCα, protein kinase alpha; NFκB, nuclear transcription factor kappa b ⁎ Corresponding author at: Department of Physiology, Faculty of Medicine, Chiang Mai University, 110 Intavaroros Rd., Sri-phum district, Muang, Chiangmai 50200, Thailand. E-mail address: [email protected] (C. Srimaroeng). https://doi.org/10.1016/j.bbadis.2019.05.013 Received 6 February 2019; Received in revised form 6 May 2019; Accepted 19 May 2019 Available online 21 May 2019 0925-4439/ © 2019 Elsevier B.V. All rights reserved. K. Sirijariyawat, et al. BBA - Molecular Basis of Disease 1865 (2019) 2342–2355 worsening glomerular and tubular structures after renal I/R [4]. Thus, induced by in vivo pre-renal, nephrotoxic, and post-renal AKI models understanding the multifactorial mechanisms involved in AKI after AMI has demonstrated a positive correlation among plasma urea and the is crucially required to seek potential targets for early intervention. decrease in functional Oat1 and Oat3 expressions on plasma membrane Renal proximal tubules play an important role in the elimination of [23]. Our previous study demonstrated that Oat1 and Oat3 share a several xenobiotics, including endogenous metabolites, drugs and common trafficking process through insulin signalling [24]. The oxi- toxins [5]. The active secretion of organic substances to the tubular dative stress induced by hyperglycaemia also impaired the regulatory lumen appears to be restricted to the basolateral membrane of proximal function of these transporters, by associating with the activation of tubule via several transporters. Among these, organic anion transpor- PKCα/NFκB and deactivation of PKCζ [25]. Hence, we hypothesised ters 1 (Oat1) and 3 (Oat3) play a significant role in rate-limiting ba- that CI and CIR could induce systemic and renal oxidative stresses, solateral uptake of organic anions due to their high expression using leading to impaired renal basolateral Oats function and their regulatory tertiary active transport process [5–7]. These two transporters initially proteins, which could potentially worsen AKI after AMI. These con- uptake anionic substrates from blood circulation into the renal epi- sequences could support the hypotheses of remote sensing signalling thelial cells against an electrochemical gradient in exchanging for the and communication between organs and organisms. Finding such an efflux of alpha-ketoglutarate (α-KG). The outwardly directed gradient early window of opportunity might be the promising target for suc- for α-KG is not only maintained by intracellular metabolic generation of cessful therapeutic intervention in AKI. α-KG through mitochondrial Kreb's cycle activity, but also is fuelled by active α-KG uptake across the basolateral membrane via a sodium di- 2. Materials and methods carboxylate cotransporter. Na+ gradient is, in turn, driven by utilising primary active Na+/K+ ATPase [5–7]. The two transporters recognise a 2.1. Chemicals broad spectrum of substrates including para-aminohippurate (PAH), ochratoxin A and uremic toxins, whereas estrone sulphate (ES) is only CelLytic MT mammalian tissue lysis/extraction reagent, unlabelled specific for Oat3 [5–7]. More recently, Oat1 was suggested to be the estrone sulphate (ES), para-aminohippurate (PAH) and 2,3,5‑triphe- centered-network which plays a key role in remote sensing and sig- nyltetrazolium chloride were purchased from Sigma Aldrich (St. Louise, nalling hypothesis by modulating essential metabolites. This includes MO, USA). Polyclonal rabbit anti-rOat1 and monoclonal mouse kreb's cycle intermediates, enterobiome-metabolites, mainly indoxyle anti‑β‑actin antibodies were purchased from Abcam (Cambridge, MA, sulphate, and key signalling molecules including prostagladins, poly- USA), while polyclonal rabbit anti-rOat3 antibody was obtained from amines and cyclic nucleotides using a novel multi-tiered systems Cosmobio (Tokyo, Japan). Polyclonal rabbit anti-PKC, phosphorylated biology approach [8]. Furthermore, previous studies reported that PKCα (p-PKCα), p65 subunit of NFκB (p65NFκB), goat anti-mouse and uremic toxins produced from organ dysfunction, including hippurate rabbit IgG horseradish peroxidase-conjugated secondary antibodies and indoleacetate, are transported by Oat1, while Oat3 was responsible were purchased from Santa Cruz (Santa Cruz, CA, USA). Monoclonal for handling 3‑carboxy‑4‑methyl‑5‑propyl‑2‑furanpropionate. Ad- mouse anti-lamin B1 and polyclonal rabbit anti-phosphorylated PKCζ ditionally, both Oat1 and Oat3 equally contributed to the transport of (p-PKCζ) were purchased from Cell Signalling (Danvers, MA, USA). indoxyl sulphate (IS) [9–12]. Subsequently, plasma endogenous anionic Polyclonal rabbit anti-PKCζ antibody was obtained from Invitrogen metabolites produced in Oat1 knockout mice including indoxyl sul- (Carlsbad, CA, USA). Monoclonal mouse anti-Na+-K+-ATPase was ob- phate, kynurenine, and xanthurenic acid as well as the predicted CAS tained from Novus Biologicals (Littleton, CO, USA). [3H]-ES (specific 5435-73-4 pharmacophore were identified using en mass untargeted activity: SA 50 Ci/mmol) and [3H]-PAH (SA
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