title: Inhibitory smads and tgf-Beta signaling in glomerular cells.
abstract: Smad6 and Smad7 are inhibitory SMADs with putative functional roles at the intersection of major intracellular signaling networks, including TGF-beta, receptor tyrosine kinase (RTK), JAK/STAT, and NF-kappaB pathways. This study reports differential functional roles and regulation of Smad6 and Smad7 in TGF-beta signaling in renal cells, in murine models of renal disease and in human glomerular diseases. Smad7 is upregulated in podocytes in all examined glomerular diseases (focal segmental glomerulosclerosis [FSGS], minimal-change disease [MCD], membranous nephropathy [MNP], lupus nephritis [LN], and diabetic nephropathy [DN]) with a statistically significant upregulation in "classical" podocyte-diseases such as FSGS and MCD. TGF-beta induces Smad7 synthesis in cultured podocytes and Smad6 synthesis in cultured mesangial cells. Although Smad7 expression inhibited both Smad2- and Smad3-mediated TGF-beta signaling in podocytes, it inhibited only Smad3 but not Smad2 signaling in mesangial cells. In contrast, Smad6 had no effect on TGF-beta/Smad signaling in podocytes and enhanced Smad3 signaling in mesangial cells. These data suggest that Smad7 is activated in injured podocytes in vitro and in human glomerular disease and participates in negative control of TGF-beta/Smad signaling in addition to its pro-apoptotic activity, whereas Smad6 has no role in TGF-beta response and injury in podocytes. In contrast, Smad6 is upregulated in the mesangium in human glomerular diseases and may be involved in functions independent of TGF-beta/Smad signaling. These data indicate an important role for Smad6 and Smad7 in glomerular cells in vivo that could be important for the cell homeostasis in physiologic and pathologic conditions.
authors.affiliation: Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Mario
authors.initials: M
authors.lastname: Schiffer
authors.forename: Lena E
authors.initials: LE
authors.lastname: Schiffer
authors.forename: Arti
authors.initials: A
authors.lastname: Gupta
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Shaw
authors.forename: Ian S D
authors.initials: IS
authors.lastname: Roberts
authors.forename: Peter
authors.initials: P
authors.lastname: Mundel
authors.forename: Erwin P
authors.initials: EP
authors.lastname: Böttinger
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism; D005920:Glomerular Mesangium / Q000378:metabolism; D005923:Glomerulosclerosis, Focal Segmental / Q000378:metabolism; D006801:Humans; D007674:Kidney Diseases / Q000378:metabolism; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology*; D008181:Lupus Nephritis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D018345:Mice, Knockout / Q000235:genetics; D009402:Nephrosis, Lipoid / Q000378:metabolism; D011506:Proteins / Q000235:genetics; D012016:Reference Values; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein; D051900:Smad3 Protein; D051905:Smad6 Protein; D051906:Smad7 Protein; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D011506:Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497802:SMAD6 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta