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-beta) has been demonstrated to promote podocyte death and the development of glomerulosclerosis. In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on TGF-beta1 induced apoptosis in podocytes. METHODS: To accomplish this we generated stable murine PKCalpha deficient podocyte cell lines and examined survival- and pro-apoptotic signaling signatures as well as caspase activation after stimulation with TGF-beta. RESULTS: After stimulation with TGF-beta we can demonstrate an enhanced and prolonged activation of PI3K/AKT and ERK1/2 in PKCalpha-knockout (PKCalpha-/-) podocytes compared to PKCalpha-wildtype (PKCalpha+/ +) podocytes, whereas proapoptotic signaling via p38MAPK is significantly reduced. Interestingly, activation of the Smad-pathway is also prolonged in the PKCalpha-/-podocytes. When we analyzed the underlying mechanisms we found a TGF-beta inducible interaction of PKCalpha with the TGF-beta-type-I-receptor (TGFbetaRI). Moreover, endocytosis assays showed that the TGFbetaRI is less internalized in PKCalpha-/- podocytes. CONCLUSION: Since we can demonstrate a key role for PKCalpha in the signaling response after stimulation with TGF-beta we conclude that PKCalpha might be an interesting target molecule as a "podocyte protective" therapy. 2009 S. Karger AG, Basel.
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-beta) has been demonstrated to promote podocyte death and the development of glomerulosclerosis. In this manuscript we analyzed the role of PKC-alpha (PKCalpha) on TGF-beta1 induced apoptosis in podocytes. METHODS: To accomplish this we generated stable murinePKCalpha deficient podocyte cell lines and examined survival- and pro-apoptotic signaling signatures as well as caspase activation after stimulation with TGF-beta. RESULTS: After stimulation with TGF-beta we can demonstrate an enhanced and prolonged activation of PI3K/AKT and ERK1/2 in PKCalpha-knockout (PKCalpha-/-) podocytes compared to PKCalpha-wildtype (PKCalpha+/ +) podocytes, whereas proapoptotic signaling via p38MAPK is significantly reduced. Interestingly, activation of the Smad-pathway is also prolonged in the PKCalpha-/-podocytes. When we analyzed the underlying mechanisms we found a TGF-beta inducible interaction of PKCalpha with the TGF-beta-type-I-receptor (TGFbetaRI). Moreover, endocytosis assays showed that the TGFbetaRI is less internalized in PKCalpha-/- podocytes. CONCLUSION: Since we can demonstrate a key role for PKCalpha in the signaling response after stimulation with TGF-beta we conclude that PKCalpha might be an interesting target molecule as a "podocyte protective" therapy. 2009 S. Karger AG, Basel.
Authors: Ruma Pengal; Adam J Guess; Shipra Agrawal; Joshua Manley; Richard F Ransom; Robert J Mourey; Rainer Benndorf; William E Smoyer Journal: Am J Physiol Renal Physiol Date: 2011-05-25
Authors: A B White; F Galbiati; M I Givogri; A Lopez Rosas; X Qiu; R van Breemen; E R Bongarzone Journal: J Neurosci Res Date: 2010-12-29 Impact factor: 4.164
Authors: Ivo Quack; Magdalena Woznowski; Sebastian A Potthoff; Romy Palmer; Eva Königshausen; Sema Sivritas; Mario Schiffer; Johannes Stegbauer; Oliver Vonend; Lars Christian Rump; Lorenz Sellin Journal: J Biol Chem Date: 2011-02-14 Impact factor: 5.157
Authors: Kirstin Worthmann; Michael Leitges; Beina Teng; Marcello Sestu; Irini Tossidou; Thomas Samson; Hermann Haller; Tobias B Huber; Mario Schiffer Journal: Am J Pathol Date: 2013-10-03 Impact factor: 4.307
Authors: Irini Tossidou; Beina Teng; Jan Menne; Nelli Shushakova; Joon-Keun Park; Jan U Becker; Friedrich Modde; Michael Leitges; Hermann Haller; Mario Schiffer Journal: PLoS One Date: 2010-04-16 Impact factor: 3.240