Podocyte apoptosis initiates progressive glomerulosclerosis in TGF-beta1 transgenic and CD2AP-knockout (CD2AP-/-) mice. It was previously shown that in both mouse models, activation of the TGF-beta pathway is the key event during development of podocyte apoptosis. Furthermore, CD2AP is an important modifier of TGF-beta-induced survival signaling via activation of the phosphoinositol 3-kinase/AKT signaling pathway. This article presents IGF-binding protein-3 (IGFBP-3) as a new modulator of apoptosis and survival signaling in glomerular podocytes. High expression of IGFBP-3 protein in the urine of diseased CD2AP-/- mice was discovered, and IGFBP-3 expression in glomerular podocytes and parietal cells was detected. IGFBP-3 can induce changes in podocyte actin cytoskeleton, leads to apoptosis in cultured murine podocytes, and can enhance TGF-beta1-induced apoptosis in vitro. For studying this process on a molecular level, proapoptotic p38 mitogen-activated protein kinase pathways and antiapoptotic phosphoinositol 3-kinase/AKT pathways were examined in cultured murine podocytes. It was found that IGFBP-3 increments the level of TGF-beta1-induced phosphorylated p38 mitogen-activated protein kinase and decreases the phosphorylation of antiapoptotic AKT. This effect is specific for the co-stimulation of IGFBP-3 with TGF-beta1 because a combination of IGFBP-3 with bone morphogenic protein-7 (BMP-7), another member of the TGF-beta superfamily, results in apoptosis opposing signaling effects with a strong increase of phosphorylated AKT and subsequent functional effects. These results demonstrate that the IGF/IGFBP axis plays an important role in the development of podocyte apoptosis by modulation of TGF-beta and BMP-7-induced pro- and antiapoptotic signals.