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.
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ABSTRACT: While emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and that the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. Major barriers to assessing for a potential AKI to CKD link have included lack of a standard pediatric AKI definition, narrow focus only on children with AKI who receive renal replacement therapy, and reliance on serum creatinine as the main biomarker to detect and diagnose AKI and CKD. Recent data have validated a multi-dimensional AKI classification system for children and have suggested chronic kidney sequelae in pediatric populations with AKI or at risk for AKI. In addition, a number of novel AKI biomarkers are being rigorously validated as early indicators of incipient CKD. Our goals for this article are to (1) review the recent changes in pediatric AKI and CKD epidemiology, (2) explore the evidence for a potential AKI to CKD link, and (3) propose new clinical and research paradigms to better elucidate the progression from AKI to CKD.Pediatric Nephrology 10/2010; 26(4):509-22. · 2.52 Impact Factor
Article: Deficiency of multidrug and toxin extrusion 1 enhances renal accumulation of paraquat and deteriorates kidney injury in mice.[show abstract] [hide abstract]
ABSTRACT: Multidrug and toxin extrusion 1 (MATE1/solute carrier 47A1) mediates cellular transport of a variety of structurally diverse compounds. Paraquat (PQ), which has been characterized in vitro as a MATE1 substrate, is a widely used herbicide and can cause severe toxicity to humans after exposure. However, the contribution of MATE1 to PQ disposition in vivo has not been determined. In the present study, we generated Mate1-deficient (Mate1-/-) mice and performed toxicokinetic analyses of PQ in Mate1-/- and wild-type (Mate1+/+) mice. After a single intravenous administration of PQ (50 mg/kg), Mate1-/- mice exhibited significantly higher plasma PQ concentrations than Mate1+/+ mice. The renal PQ concentration was markedly increased in Mate1-/- mice compared with Mate1+/+ mice. The subsequent nephrotoxicity of PQ were examined in these mice. Three days after intraperitoneal administration of PQ (20 mg/kg), the transcript levels of N-acetyl-β-D-glucosaminidase (Lcn2) and kidney injury molecule-1 (Kim-1) in the kidney were remarkably enhanced in the Mate1-/- mice. This was accompanied by apparent difference in renal histology between Mate1-/- and Mate1+/+ mice. In conclusion, we demonstrated that Mate1 is responsible for renal elimination of PQ in vivo and the deficiency of Mate1 function confers deteriorated kidney injury caused by PQ in mice.Molecular Pharmaceutics 12/2011; 8(6):2476-83. · 4.78 Impact Factor