TGF-beta signal transduction in chronic kidney disease

Abstract

Transforming growth factor (TGF)-beta is a central stimulus of the events leading to chronic progressive kidney disease, having been implicated in the regulation of cell proliferation, hypertrophy, apoptosis and fibrogenesis. The fact that it mediates these varied events suggests that multiple mechanisms play a role in determining the outcome of TGF-beta signaling. Regulation begins with the availability and activation of TGF-beta and continues through receptor expression and localization, control of the TGF-beta family-specific Smad signaling proteins, and interaction of the Smads with multiple signaling pathways extending into the nucleus. Studies of these mechanisms in kidney cells and in whole-animal experimental models, reviewed here, are beginning to provide insight into the role of TGF-beta in the pathogenesis of renal dysfunction and its potential treatment.

Figure 1

Domain structure of Smad3. Potential phosphoacceptor residues are indicated by the symbols; the corresponding numbers indicate the amino acid positions in the sequence.

Figure 2

Signal transduction pathways from the cell membrane to the nucleus discussed in this article. Solid lines with arrows indicate positive effects; broken lines indicate inhibitory effects. Tsp, thrombospondin; HA, hyaluronan; 1, TGF-beta receptor (TbetaR) I; 2, TbetaR II; PI3K, Phosphatidylinositol-3-kinase; SARA, Smad anchor for receptor activation; Dab2, disabled-2; TAK, TGF-beta-activated kinase; FAK, focal adhesion kinase; PKC, protein kinase C; UBQ, ubiquitin; Smad3-cP, Smad3 phosphorylated on the C-terminus; Smad3-LP-cP, Smad3 phosphorylated at the linker region and at the C-terminus; CTGF, connective tissue growth factor; ECM, extracellular matrix. Three inhibitory pathways, involving (respectively) bone morphogenetic protein-7, hepatocyte growth factor and the nuclear receptor-associated hormones, are not shown because they act at multiple sites in the Smad2/Smad3-mediated pathway. The inclusion of arrows depicting both enhancing and inhibiting effects for Smad linker region phosphorylation indicate that the implications of these phosphorylation events remain poorly defined.

Figure 3

Mechanisms by which TGF-beta induces chronic kidney disease.