MP252
LYSOPHOSPHATIDIC ACID PROTECTS AGAINST ENDOTOXEMIA-ASSOCIATED ACUTE KIDNEY INJURY

INTRODUCTION AND AIMS: Acute kidney injury (AKI) represents a worrying public health problem worldwide with high mortality rate and increased progression of underlying chronic kidney disease. To date the most common causal factor of AKI in intensive care unit patients is septic shock but the underlying mechanisms remain unclear and no targeted therapies exist for sepsis-induced AKI. Lysophosphatidic acid (LPA) is a bioactive lipid acting through specific G-protein coupled receptors. In vivo administration of LPA was reported to mitigate the inflammation and injuries caused by bacterial endotoxemia in liver and lung. The objective of the present study was to determine whether exogenous and/or endogenous LPA might protect against sepsis-associated AKI.

METHODS: C57BL/6 mice were treated with LPA 18:1 (5mg/kg, i.p.) 1 hour before being injected with the endotoxin lipopolysaccharide (LPS) and AKI was analyzed after 24h.

RESULTS: LPA significantly mitigated the elevation of plasma urea and creatinine caused by LPS. In kidney, LPA pre-treatment significantly lessened the up-regulated expression of inflammatory cytokines (IL-6, TNFa, MCP-1), and completely prevented the down-regulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) caused by LPS. LPA also prevented some LPS-mediated alterations of renal mitochondria ultrastructure. In vitro, pre-treatment with LPA 18:1 (10 µM) significantly attenuated LPS-induced up-regulation of the pro-inflammatory cytokines (TNFa and MCP-1) in RAW264 macrophages. Moreover, it was observed that LPS led to the reduction of urinary LPA concentration that was associated with a reduction in LPA anabolic enzymes (autotaxin and acylglycerol kinase), and an elevation in LPA catabolic enzyme (lipid phosphate phosphatase 2) expression in kidney cortex.

CONCLUSIONS: In conclusion, the present work demonstrates that the protective action of exogenous LPA against organs inflammation and injuries caused by bacterial endotoxemia can be extended to kidney. Moreover, the observation that LPS reduces the renal production of LPA suggests that sepsis-associated AKI could be mediated, at least in part, by alleviation of the protective action of endogenous LPA.