Apoptosis in podocytes induced by TGF-beta and Smad7.
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.
Schiffer
M
M
Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Bitzer
M
M
Roberts
I S
IS
Kopp
J B
JB
ten Dijke
P
P
Mundel
P
P
Böttinger
E P
EP
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D004195:Disease Models, Animal; D005920:Glomerular Mesangium / Q000473:pathology; D005923:Glomerulosclerosis, Focal Segmental / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007678:Kidney Glomerulus / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D051906:Smad7 Protein; D015534:Trans-Activators / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D016328:NF-kappa B; C497806:SMAD7 protein, human; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases