Regulatory role of eicosanoids in extracellular matrix overproduction induced by long-term exposure to high glucose in cultured rat mesangial cells

Summary Accumulation of extracellular matrix in the mesangium and altered renal eicosanoid synthesis are two prominent features of diabetic glomerular disease. We investigated the relationship between eicosanoid and extracellular matrix production in rat mesangial cells cultured under high glucose vs normal glucose conditions. Long-term exposure of rat mesangial cells to high glucose, but not to iso-osmolar mannitol, significantly increased extracellular matrix accumulation and gene expression and transforming growth factor- (TGF-) mRNA levels, and decreased prostaglandin (PG) E₂ synthesis without affecting production of either thromboxane (TX) B₂ or PGF₂, with respect to cells incubated in normal glucose. Addition of exogenous PGE₂ resulted in a dose-dependent reduction of matrix protein and mRNA levels and TGF- gene expression in cells cultured in either normal or high glucose conditions, whereas exposure to exogenous PGF₂ produced a significant increment in matrix production and matrix and TGF- gene expression in cells grown in normal glucose, but only a slight increase in those cultured in high glucose. Stimulation of endogenous endoperoxide metabolism towards PGE₂ and PGF₂ synthesis with FCE-22,178, a drug originally developed as TXA₂ synthase inhibitor, resulted in a dose-dependent decrease in matrix accumulation and matrix and TGF- gene expression which was suppressed by co-incubation with the cyclo-oxygenase inhibitor feno-profen blocking the FCE-22,178-enhanced PG production. In both cell lines, the rate of synthesis of TXA₂ was very low and the selective blockade of its synthesis (by two other TXA₂ synthase inhibitors, OKY-046 and Ridogrel) or action (by the TXA₂ receptor antagonist BM-13,177) did not alter matrix production or TGF- mRNA levels. These results suggest that the cyclo-oxygenase pathway is involved in the regulation of matrix changes induced by high glucose in rat mesangial cells; the reduced production of PGE₂ may enhance the synthesis or potentiate the effect of stimulators of ECM formation such as TGF-, whereas TXA₂ does not appear to be involved. These data also indicate that glucose-enhanced mesangial matrix accumulation may be prevented by exogenous PGE₂ or by drugs capable of increasing endogenous PGE₂ synthesis.Abbreviations AGE Advanced glycosylation end-products - ECM extracellular matrix - PG prostaglandin - RMC rat mesangial cells - TGF- transforming growth factor- - TX thromboxane - Cox cyclo-oxygenase