FK506-induced endothelin release by cultured rat mesangial cells

Renal damage is a major side effect of the macrolide immunosuppressant FK 506. Although little is known about the underlying mechanism of FK 506 nephrotoxicity, available data suggest that it may be associated with a disturbance in renal hemodynamics, possibly brought about by alterations in the production of vasoactive substances such as endothelin-1 (ET-1). We have investigated the release of ET-1 from primary renal mesangial cells in culture. Mesangial cells derived from rat renal cortex were exposed to a range of FK 506 concentrations (10(-10) to 10(-6) M) or vehicle for up to 6 h. FK 506 caused a significant dose-related increase in ET release. This effect was dependent on cell density and was blocked by co-incubation with FPL 65620, an FK 506 analogue that binds to the FK binding protein (FKBP) and inhibits the immunosuppressive activity of FK 506. These data suggest that mesangial cell ET may play a role in FK 506 nephrotoxicity and that the effect of FK 506 on ET release may be mediated through the FKBP.