Abstract P144: DHA is a Superior Treatment Over 12/15-lipoxygenase Inhibition in LPS-induced Acute Kidney Injury via Increased Resolvin D2 and IL-10 Levels

Abstract

Acute kidney injury (AKI) is characterized by loss of kidney function and is often associated with high mortality rate. The polyunsaturated, omega-3 fatty acid, docosahexaenoic acid (DHA), has a promising role in preventing AKI; however; DHA reno-protective mechanism remains unclear. Our aim is to investigate whether and how DHA attenuates lipopolysaccharide (LPS)-induced AKI. Four groups of wild type C57BL/6 (WT) mice were used; control, LPS injected (4 mg/kg i.p), LPS treated with the 12/15-lipoxygenase (12/15-LO) inhibitor baicalein (20 mg/kg i.p for 6 days) and LPS treated with DHA (50 mg/kg i.p for 6 days). LPS-injected mice showed significant elevation in markers of renal injury as urinary excretion levels of protein, podocalyxin and albumin were elevated compared to WT untreated mice (albuminuria was 112±4 vs. 8±1 μg/day and podocalyxin was 3.5±0.6 vs. 0.6±0.1 μg/day in LPS injected mice vs. control WT, P< 0.05). The elevation in renal injury markers were also associated with increases in urinary excretion of thiobarbituric acid reactive substance (TBARs), as a marker of oxidative stress and monocyte chemoattractant protein-1 (MCP-1), as a marker of inflammation, in LPS injected mice. Treatment of LPS injected mice with either DHA or baicalein significantly reduced markers of renal injury, inflammation and oxidative stress. DHA or baicalein treatment also significantly reduced the elevation in renal mRNA expression levels of intercellular adhesion molecule 1 (ICAM-1) and tumor necrosis factor-α (TNF-α) in LPS injected mice. DHA was superior over baicalein in reducing renal expression of Interleukin-6 (IL-6) and IL-1β and in increasing the renal expression of the anti-inflammatory cytokine IL-10 in LPS injected mice. DHA reduced renal tubular necrosis and vaculated cells and lowered renal expression of CD45, a marker of leucocyte adhesion, in LPS injected mice. DHA also restored the decrease in plasma resolvin D2 (RvD2) in LPS injected mice. In conclusion, our data suggest that 12/15-LO activation is involved in LPS-induced acute kidney injury and DHA is a superior treatment over 12/15-LO inhibitor in preventing LPS-induced kidney injury, at least in part, via 12/15-LO-induced resolvin D2.