title: Effects of valproic acid and dexamethasone administration on early bio-markers and gene expression profile in acute kidney ischemia-reperfusion injury in the rat.
abstract: Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this investigation was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Under general anesthesia, left renal ischemia was induced in Wister rats by occluding renal artery for 45 minutes, followed by reperfusion and right nephrectomy. Thirty minutes prior to ischemia, rats (n = 8/group) received Valproic Acid (150 mg/kg; VPA), Dexamethasone (3 mg/kg; Dex) or Vehicle (saline) intraperitoneally. Animals were sacrificed at 3, 24 or 120 h post-IR. Plasma creatinine (mg/dL) at 24 h was reduced (P<0.05) in VPA (2.7±1.8) and Dex (2.3±1.2) compared to Vehicle (3.8±0.5) group. At 3 h, urine albumin (mg/mL) was higher in Vehicle (1.47±0.10), VPA (0.84±0.62) and Dex (1.04±0.73) compared to naïve (uninjured/untreated control) (0.14±0.26) group. At 24 h post-IR urine lipocalin-2 (μg/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (9.61-11.36) compared to naïve group (0.67±0.29); also, kidney injury molecule-1 (KIM-1; ng/mL) was higher (P<0.05) in VPA, Dex and Vehicle groups (13.7-18.7) compared to naïve group (1.7±1.9). Histopathology demonstrated reduced (P<0.05) ischemic injury in the renal cortex in VPA (Grade 1.6±1.5) compared to Vehicle (Grade 2.9±1.1). Inflammatory cytokines IL1β and IL6 were downregulated and anti-apoptotic molecule BCL2 was upregulated in VPA group. Furthermore, kidney DNA microarray demonstrated reduced injury, stress, and apoptosis related gene expression in the VPA administered rats. VPA appears to ameliorate kidney IR injury via reduced inflammatory cytokine, apoptosis/stress related gene expression, and improved regeneration. KIM-1, lipocalin-2 and albumin appear to be promising early urine biomarkers for the diagnosis of AKI.
authors.affiliation: Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, United States of America.
authors.forename: Ryan W
authors.initials: RW
authors.lastname: Speir
authors.affiliation: Environmental Health Program, US Army Center for Environmental Health Research, Fort Detrick, Maryland, United States of America.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Stallings
authors.affiliation: Department of Pathology, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, United States of America.
authors.forename: Jared M
authors.initials: JM
authors.lastname: Andrews
authors.affiliation: Department of Pathology, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, United States of America.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Gelnett
authors.affiliation: Department of Surgery, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, United States of America.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Brand
authors.affiliation: Department of Clinical Investigation, Madigan Army Medical Center, Tacoma, Fort Lewis, Washington, United States of America.
authors.forename: Shashikumar K
authors.initials: SK
authors.lastname: Salgar
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage*; D017209:Apoptosis; D015415:Biomarkers / Q000652:urine; D015815:Cell Adhesion Molecules / Q000652:urine; D003907:Dexamethasone / Q000008:administration & dosage*; D004353:Drug Evaluation, Preclinical; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D000071068:Lipocalin-2; D054834:Lipocalins / Q000652:urine; D008297:Male; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000652:urine; D059467:Transcriptome; D014635:Valproic Acid / Q000008:administration & dosage*
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D003907:Dexamethasone; D000071068:Lipocalin-2; D054834:Lipocalins; D019253:Proto-Oncogene Proteins c-bcl-2; D014635:Valproic Acid; C110936:Havcr1 protein, rat; C097278:Lcn2 protein, rat