Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 108, Issue 6, Pages 807-816Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI12367
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- NIDDK NIH HHS [R01 DK056077, R01 DK060043, DK56077-01] Funding Source: Medline
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Primary and secondary forms of focal segmental glomerulosclerosis (FSGS) are characterized by depletion of podocytes and constitute a central manifestation of chronic progressive glomerular diseases. Here we report that podocytes undergo apoptosis at early stages in the course of progressive glomerulosclerosis in TGF-beta1 transgenic mice. Apoptosis is associated with progressive depletion of podocytes and precedes mesangial expansion. Smad7 protein expression is strongly induced specifically in damaged podocytes of transgenic mice and in cultured murine podocytes treated with TGF-beta. TGF-beta1 and Smad7 each induce apoptosis in podocytes, and their coexpression has an additive effect. Activation of p38 MAP kinase and caspase-3 is required for TGF-beta -mediated apoptosis, but not for apoptosis induced by Smad7. Unlike TGF-beta, Smad7 inhibits nuclear translocation and transcriptional activity of the cell survival factor NF-kappaB. Our results suggest a novel functional role for Smad7 as amplifier of TGF-beta -induced apoptosis in podocytes and a new pathomechanism for podocyte depletion in progressive glomerulosclerosis.
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