Mechanisms of BIGH3-Mediated Apoptosis in Renal Cells

Transforming Growth Factor Beta-Induced Gene Human Clone 3 (BIGH3) is a secreted extracellular matrix protein. BIGH3 synthesis is greatly increased by Transforming Growth Factor Beta 1 (TGFβ1). Our previous studies explored the role of BIGH3 in diabetic nephropathy, where macrophage-derived TGFβ1 was shown to increase BIGH3 synthesis in Renal Proximal Tubule Epithelial Cells (RPTEC) and significantly increase BIGH3-mediated apoptosis (BMA) in RPTEC. BIGH3 was shown to have a dose-dependent effect upon RPTEC apoptosis. BMA in RPTEC apoptosis when treated with macrophage-derived TGFβ1 was blocked by antibodies specific to TGFβ1 and BIGH3, as well as pharmaceutical inhibition of the TGFβ1 receptor. This current study demonstrates the mechanism of BMA in RPTEC, a series of stepwise interactions that requires proteolytic cleavage of the C-terminus and liberation of the EPDIM integrin-binding sequence found in BIGH3 C-terminus, and ligation of EPDIM by α3β1 integrin in RPTEC. These findings further clarify the mechanism of action of BIGH3-mediated apoptosis and potentiate new avenues of therapeutic intervention for the diabetic patient.