Renoprotective Effects of Valproic Acid and Dexamethasone in Acute Kidney Ischemia-Reperfusion Injury

Introduction: Renal ischemia-reperfusion (IR) causes acute kidney injury (AKI) with high mortality and morbidity. The objective of this study was to ameliorate kidney IR injury and identify novel biomarkers for kidney injury and repair. Methods: Left renal ischemia was induced in rats by clamping 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 3h, 24h or 120h post- IR and blood, urine and kidney were collected. Results: Serum creatinine (mg/dL) at 24 h IR in VPA (2.71.8) and Dex (2.31.2) was reduced (P<0.05) compared to Vehicle (3.80.5). At 3h post-IR, urine albumin (mg/ml) was higher in Vehicle (1.470.10), VPA (0.840.62) and Dex (1.040.73) compared to uninjured/untreated control (0.140.26) group. At 24h post-IR urine Lipocalin-2 (g/ml) was significantly higher (P<0.05) in VPA, Dex and Vehicle groups (9.61-11.36) compared to uninjured/untreated control (0.67o.29); also, Kidney Injury Molecule-1 (KIM-1; ng/ml) was significantly higher in VPA, Dex and Vehicle groups (13.7-18.7) compared uninjured/untreated control (1.71.9). KIM-1 levels were significantly (P<0.05) higher in all groups compared to uninjured/untreated control levels. Histopathology at 3h post IR demonstrated (P<0.05) reduction in ischemic injury in the renal cortex in VPA (Grade 1.6 1.5) compared to Vehicle (Grade 2.91.1) group. Inflammatory cytokines IL1 and IL6 were down-regulated in VPA and Dex groups. BCL2 was higher in VPA group. DNA microarray analysis demonstrated reduced stress response and injury, and improved recovery related gene expression in the kidneys of VPA treated animals. Conclusions: VPA administration reduced kidney IR injury and improved regeneration. KIM-1 and Lipocalin-2 appear to be promising early urine biomarkers of acute ischemic kidney injury.

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Speir RW, Stallings JD, Andrews JM, Gelnett MS, Brand TC, Salgar SK