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Modification of the Transcriptomic Response to Renal Ischemia

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Modification of the Transcriptomic Response to Renal Ischemia Kidney International, Vol. 64 (2003), pp. 480–492 CELL BIOLOGY–IMMUNOLOGY–PATHOLOGY Modification of the transcriptomic response to renal ischemia/ reperfusion injury by lipoxin analog NIAMH E. KIERAN,1 PETER P. DORAN,1 SUSAN B. CONNOLLY,MARIE-CLAIRE GREENAN, DEBRA F. HIGGINS,MARTIN LEONARD,CATHERINE GODSON,CORMAC T. TAYLOR, ANNA HENGER,MATTHIAS KRETZLER,MELISSA J. BURNE,HAMID RABB, and HUGH R. BRADY Human Genomics and Bioinformatics Research Unit, Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Mater Misericordiae Hospital, Dublin 7 and the Dublin Molecular Medicine Centre, Ireland; Medizinische Poliklinik, Ludwig-Maximilians-Universitat, Munchen, Germany; and Nephrology Division, Johns Hopkins University Hospital, Baltimore, MD, USA Modification of the transcriptomic response to renal ischemia/ (e.g., aquaporin-1) and the zinc metalloendopeptidase meprin- reperfusion injury by lipoxin analog. 1␤ implicated in renal remodeling. Background. Lipoxins are lipoxygenase-derived eicosanoids Conclusion. Treatment with the lipoxin analog 15-epi-16- with anti-inflammatory and proresolution bioactivities in vitro (FPhO)-LXA4-Me prior to injury modified the expression of and in vivo. We have previously demonstrated that the stable many differentially expressed pathogenic mediators, including synthetic LXA4 analog 15-epi-16-(FPhO)-LXA4-Me is reno- cytokines, growth factors, adhesion molecules, and proteases, protective in murine renal ischemia/reperfusion injury, as suggesting a renoprotective action at the core of the pathophys- gauged by lower serum creatinine, attenuated leukocyte infil- iology of acute renal failure (ARF). Importantly, this lipoxin- tration, and reduced morphologic tubule injury. modulated transcriptomic response included many genes ex- Methods. We employed complementary oligonucleotide mi- pressed by renal parenchymal cells and was not merely a reflection croarray and bioinformatic analyses to probe the transcripto- of a reduced renal mRNA load resulting from attenuated leu- mic events that underpin lipoxin renoprotection in this setting. kocyte recruitment. The data presented herein suggest a frame- Results. Microarray-based analysis identified three broad work for understanding drivers of kidney injury in ischemia/ categories of genes whose mRNA levels are altered in response reperfusion and the molecular basis for renoprotection by li- to ischemia/reperfusion injury, including known genes previously poxins in this setting. implicated in the pathogenesis of ischemia/reperfusion injury [e.g., intercellular adhesion molecule-1 (ICAM-1), p21, KIM-1], known genes not previously associated with ischemia/reper- Ischemic acute renal failure (ARF) remains a formida- fusion injury, and cDNAs representing yet uncharacterized genes. Characterization of expressed sequence tags (ESTs) dis- ble clinical problem that is associated with high morbid- played on microarrays represents a major challenge in studies ity and mortality [1, 2]. The pathophysiology of ARF is of global gene expression. A bioinformatic annotation pipeline complex and multipronged and includes persistent intra- successfully annotated a large proportion of ESTs modulated renal vasoconstriction, hypoxic injury to microvascular during ischemia/reperfusion injury. The differential expression endothelial cells and tubule epithelial cells, and leuko- of a representative group of these ischemia/reperfusion injury– modulated genes was confirmed by real-time polymerase chain cyte-mediated cytotoxicity [1–3]. Despite the impressive reaction. Prominent among the up-regulated genes were clau- efficacy of agents that target these events in experimental din-1, -3, and -7, and ADAM8. Interestingly, the former re- models, none has proved as effective as monotherapy in sponse was claudin-specific and was not observed with other randomized, controlled clinical trials [1, 2]. Accordingly, claudins expressed by the kidney (e.g., claudin-8 and -6) or attention has shifted toward therapeutic interventions indeed with other components of the renal tight junctions (e.g., occludin and junctional adhesion molecule). Noteworthy among that simultaneously target two or more of the aforemen- the down-regulated genes was a cluster of transport proteins tioned pathophysiologic events. Lipoxins are lipoxygenase-derived arachidonate me- tabolites that are formed predominantly through cell- 1 Dr. Kieran and Dr. Doran contributed equally to this work. cell interactions in many human and experimental in- Key words: lipoxins, acute renal failure, ischemia, microarrays, gene flammatory, hypersensitivity, and vascular diseases [4, 6]. chips, bioinformatics, claudins, meprin, ADAM8. The spectrum of bioactivities reported for lipoxins in Received for publication October 14, 2002 vitro and in vivo suggests that these lipid mediators may and in revised form January 14, 2003 be protective in renal ischemia/reperfusion injury. Lipox- Accepted for publication March 21, 2003 ins are potent intrarenal vasodilators that inhibit poly- 2003 by the International Society of Nephrology morphonuclear cells (PMNs) chemotaxis, adhesion and 480 Kieran and Doran et al: Transcriptomic response to renal ischemia-reperfusion injury 481 migration across the endothelium and epithelium, pro- METHODS mote clearance of apoptotic PMNs, and modulate several Experimental ischemia/reperfusion injury cytokine responses [4–13]. Cyclooxygenase-2 (COX-2), ARF was induced in National Institutes of Health when acetylated by aspirin, catalyzes the generation of (NIH) Swiss mice (25 to 35 g) by clamping both renal 15R-HETE from arachadonic acid [4]. 15R-HETE is pedicles for 30 minutes, followed by 24 hours of reperfu- then converted by leukocytes to 15R epimers of lipoxins sion [21]. Animals received a 15 ␮g single bolus injection [aspirin-triggered lipoxins (ATLs)] during cell interac- of 15-epi-16-(FPhO)-LXA4-Me or an equivalent volume tions [3]. ATLs share many of the anti-inflammatory and of its vehicle into the inferior vena cava 10 minutes prior proresolution properties of native lipoxins in vitro [4]. to clamping. Sham-operated animals served as controls. Analogs of LXA4 and LXB4 (the major mammalian li- The influence of the lipoxin analog on changes in renal poxin) and of ATLs have been synthesized that are rela- function, morphology, and PMN infiltration in these tively resistant to degradation [4]. mice has been previously reported [21]. As a second Importantly, they display many of the biologic proper- model of ARF, murine folic acid–induced acute tubular ties of native lipoxins and ATLs in vitro and are potential necrosis (ATN) was used. This model, as previously de- prototype therapeutics [14]. Native LXA4, ATLs, and scribed [22], involved administering 250 mg/kg body several synthetic lipoxin analogs have already been dem- weight of folic acid by intraperitoneal injection. Animals onstrated to have impressive anti-inflammatory and pro- were sacrificed at 0, 3, 6, 24, and 72 hours. Serum creati- resolution activity in experimental dermal inflammation, nine increased approximately four- to five-fold over the glomerulonephritis, and hind limb–induced second or- course of the experiment [22]. gan injury [15–20]. Taqman-PCR We have previously demonstrated the protective effect Total RNA was isolated from murine kidneys and of a stable analog of aspirin-triggered 15-epi-LXA , 15- 4 spleens using Trizol solution (Gibco, Paisley, UK) ac- epi-16-(FPhO)-LXA -Me in experimental murine ARF 4 cording to the manufacturer’s instructions. For real-time in vivo as manifested by significant functional and mor- polymerase chain reaction (PCR) analysis of murine tis- phologic protection and by blunted chemokine and cyto- sue, chromosomal DNA was removed from total RNA kine responses [21]. The latter experiments focused on using DNase I. DNAse-treated RNA (2 ␮g) was tran- a relatively small number of mediators that have pre- scribed to cDNA using standard procedures. Real-time viously been implicated in the pathogenesis of ischemia/ PCR was performed on a TaqMan ABI 7700 Sequence reperfusion injury or have been identified as players in Detection System (Applied Biosystems, Weiterstadt, lipoxin-mediated cytoprotection in other systems. While Germany) using heat-activated TaqDNA polymerase such targeted approaches can shed valuable new light on (Amplitaq Gold; Applied Biosystems, Weiterstadt, Ger- molecular mechanisms of disease, they are, by definition, many) [23]. After an initial hold of 2 minutes at 50ЊC biased by and dependent on, previous work in the bio- and 10 minutes at 95ЊC, the samples were cycled 40 times logic system of interest or in related systems. With ad- at 95ЊC for 15 seconds and 60ЊC for 60 seconds. Target vances in transcriptomics, it is now apparent that even gene forward and reverse primers and probes were de- simple perturbations of single-cell systems induce com- signed using Primer Express 1.5 software (Applied Bio- plex and highly coordinated changes in gene expression. systems, Foster City, CA, USA). Commercially available By applying these emerging technologies to well-charac- predeveloped TaqMan assay reagents (PDARs) were terized disease models it should be possible to decipher, in used for the internal standards human glycerin-aldehyde- 3-phosphate-dehydrogenase (GAPDH) and 18S ribo- an unbiased fashion, the full spectrum of genomic events somal RNA (18S rRNA). All primers and probes were that underpin organ dysfunction and the complex sym- obtained
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