PKC-alpha Modulates TGF-β Signaling and Impairs Podocyte Survival
Background: Progressive loss of podocytes has been documented as an early lesion in the development of glomerular disease. In a variety of glomerular diseases, including diabetic nephropathy the activation of transforming growth factor-beta (TGF-β) has been demonstrated to promote podocyte death and the development of glomerulosclerosis. In this manuscript we analyzed the role of PKC-alpha (PKCα) on TGF-β1 induced apoptosis in podocytes. Methods: To accomplish this we generated stable murine PKCα deficient podocyte cell lines and examined survival- and pro-apoptotic signaling signatures as well as caspase activation after stimulation with TGF-β. Results: After stimulation with TGF-β we can demonstrate an enhanced and prolonged activation of PI3K/AKT and ERK1/2 in PKCα-knockout (PKCα-/-) podocytes compared to PKCα-wildtype (PKCα+/ +) podocytes, whereas proapoptotic signaling via p38MAPK is significantly reduced. Interestingly, activation of the Smad-pathway is also prolonged in the PKCα-/-podocytes. When we analyzed the underlying mechanisms we found a TGF-β inducible interaction of PKCα with the TGF-β-type-I-receptor (TGFβRI). Moreover, endocytosis assays showed that the TGFβRI is less internalized in PKCα-/- podocytes. Conclusion: Since we can demonstrate a key role for PKCα in the signaling response after stimulation with TGF-β we conclude that PKCα might be an interesting target molecule as a “podocyte protective” therapy.