Human munc13 is a diacylglycerol receptor that induces apoptosis and may contribute to renal cell injury in hyperglycemia

We have previously shown that human munc13 (hmunc13) is up-regulated by hyp erglycemia under in vitro conditions in human mesangial cell cultures. The purpose of the present study was to determine the cellular function of hmun c13. To do this, we have investigated the subcellular localization of hmunc 13 in a transiently transfected renal cell line, opossum kidney cells. We h ave found that hmunc13 is a cytoplasmic protein and is translocated to the Golgi apparatus after phorbol ester stimulation. In addition, cells transfe cted with hmunc13 demonstrate apoptosis after treatment with phorbol ester, but cells transfected with an hmunc13 deletion mutant in which the diacylg lycerol (C1) binding domain is absent exhibit no change in intracellular di stribution and no induction of apoptosis in the presence of phorbol ester s timulation. We conclude that both the diacylglycerol-induced translocation and the apoptosis represent functional activity of hmunc13. We have also de monstrated that munc13-1 and munc13-2 are localized mainly to cortical epit helial cells in rat kidney and both are overexpressed under conditions of h yperglycemia in a streptozotocin-treated diabetic rat model. Taken together , our data suggest that hmunc13 serves as a diacylglycerol-activated, PKC-i ndependent signaling pathway capable of inducing apoptosis and that this pa thway may contribute to the renal cell complications of hyperglycemia.