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.

Late intervention with the small molecule BB3 mitigates postischemic kidney injury

“…The cells of the renal proximal tubule are under a large metabolic demand due to their role in bulk reabsorption of glomerular filtrate, rendering the epithelial cells lining this segment highly susceptible to injury after IR. Tubular epithelial cells respond to such an insult with shedding of the brush border or cell death due to either necrosis or apoptosis (28,32,43). Identifying an effective strategy to promote tubular survival and/or regeneration is essential for minimizing kidney damage and accelerating repair and recovery after AKI.…”

“…Specimens were examined in a blinded manner under light microscopy, as previously described (43) with minor modifications. Briefly, three high-power fields (at ϫ40 magnification, representing ϳ50 tubules) from the cortex and outer medulla of each kidney were examined and graded for predominant injury patterns including tubular necrosis and tubular dilation (43). Overall kidney injury was graded on a scale of 0 -4.…”

Cysteine‐rich protein 61, a specific ultra‐early biomarker in kidney ischemia/reperfusion injury

“…We searched the public microarray database GEO (Gene Expression Omnibus, http://www.ncbi.nlm.nih.gov/geo/) for AKI‐related samples. Raw data (CEL file) of GSE58438 and series GSE52004 were downloaded from GEO database. GSE58438 derived total kidney messenger RNA (mRNA) from rat unilateral I/R and GSE52004 came from four different types of Trap‐mRNA from mice bilateral I/R.…”

Mining kidney toxicogenomic data by using gene co-expression modules

“…We further evaluated the relevance of frequently co-expressed genes with Havcr1 , using an external dataset (GSE58438) collected from Gene Expression Omnibus (GEO). In this dataset, ischemic kidney injury was produced by clamping the renal artery [ 55 ]. This dataset contains five control replicates and five replicates of animals collected at 1 and 5 days after ischemic kidney injury.…”