Inhibition of type I and III IP3Rs by TGF-β is associated with impaired calcium release in mesangial cells

Inositol 1,4,5-trisphosphate receptors (IP3Rs) mediate cytosolic free calcium concentration ([Ca2+]c) signals in response to a variety of agonists that stimulate mesangial cell contraction and proliferation. In the present study, we demonstrate that mesangial cells express both type I and III IP3Rs and that these receptors occupy different cellular locations. Chronic treatment with transforming growth factor-β1 (TGF-β1; 10 ng/ml, 24 h) leads to downregulation of both type I and III IP3Rs as measured by immunoblot and confocal analysis. TGF-β1 treatment does not affect IP3 levels, and downregulation of type I IP3R is not due to enhanced degradation of the protein, as the half-life of type I IP3R is unchanged in the presence or absence of TGF-β1. Functional effects of TGF-β1-induced downregulation of the IP3Rs were evaluated by measuring [Ca2+]c changes in response to epidermal growth factor (EGF) in intact cells and sensitivity of [Ca2+]c release to IP3in permeabilized cells. TGF-β1 pretreatment led to a s...