Fibrate treatment of eEOCs in murine AKI.

BACKGROUND: Early endothelial outgrowth cells (eEOCs) protect mice from acute kidney injury (AKI). Peroxisome proliferator-activated receptor-alpha (PPAR-α) has been shown to mediate renoprotective effects under different experimental conditions. The aim of the study was to investigate consequences of fibrate treatment of murine eEOCs in a cell-based therapeutic approach to AKI.

METHODS: Male C57/Bl6N mice, subjected to unilateral renal ischemia (40 min) post-uninephrectomy, were systemically injected with 0.5 × 10(6) untreated or fenofibrate (FF 1, 5, 10 or 50 μm)/clofibrate (CF 1 mm) pretreated syngeneic murine eEOCs. Renal function and morphology were analyzed 48 h later. Cellular consequences of eEOC treatment with fibrates (FF 1, 5, 10, 50 μm, CF 1 mm) were evaluated using different in vitro assays (direct cell migration, apoptosis/necrosis, ELISA studies).

RESULTS: Administration of untreated eEOCs did not protect mice from AKI. Injection of eEOCs treated with CF (1 mm) or FF 50 μm did not result in any protection from ischemia-induced renal dysfunction. In vitro analysis showed reduced cellular secretion of vasoprotective vascular endothelial growth factor (VEGF), an effect that was more pronounced with CF; FF increased percentages of apoptotic/necrotic eEOCs, and both substances failed to stimulate migration of cultured cells. With lower FF concentrations (1, 5, 10 μm) cell survival was increased and 10 μm FF stimulated VEGF secretion. In vivo administration of FF-treated eEOCs (10 μm) also did not result in any renoprotective effect.

CONCLUSION: PPAR-α activation using fibrates does not stimulate renoprotective effects of syngeneic murine eEOCs in ischemic AKI, although lower fibrate concentrations significantly activate eEOCs in vitro.