title: Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition.
abstract: Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 (Havcr1) and lipocalin 2 (Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-1, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-1 and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI.
authors.affiliation: Nephrology Division, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Gang Jee
authors.initials: GJ
authors.lastname: Ko
authors.forename: Dmitry N
authors.initials: DN
authors.lastname: Grigoryev
authors.forename: Douglas
authors.initials: D
authors.lastname: Linfert
authors.forename: Hye Ryoun
authors.initials: HR
authors.lastname: Jang
authors.forename: Tonya
authors.initials: T
authors.lastname: Watkins
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.forename: Lorraine
authors.initials: L
authors.lastname: Racusen
authors.forename: Hamid
authors.initials: H
authors.lastname: Rabb
mesh_terms: D000208:Acute Disease; D000209:Acute-Phase Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005355:Fibrosis; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D053263:Gene Regulatory Networks; D000072596:Hepatitis A Virus Cellular Receptor 1; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007668:Kidney / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D007674:Kidney Diseases / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D000209:Acute-Phase Proteins; D015415:Biomarkers; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D000071068:Lipocalin-2; D054834:Lipocalins; D008565:Membrane Proteins; D015513:Oncogene Proteins; C071332:Lcn2 protein, mouse