TGF-β1 modulates podocyte migration by regulating the expression of integrin-β1 and -β3 through different signaling pathways.

Objective: Podocyte migration may lead foot process effacement and proteinuria. Transforming growth factor-β1 (TGF-β1) and integrins are involved in the adhesion and migration of cells. However, the crosstalk of TGF-β1 and integrins is unclear. Here, we examined how TGF-β1 regulates the expression of integrin-β1 and -β3 to modulate podocyte adhesion and migration.

Methods: Podocytes were exposed to TGF-β1 and/or the inhibitors of Smad2/3, ERK and p38, then the expression of integrin-β1 and -β3 was assessed by Real-time PCR and western blot analyses. Podocyte adhesion and migration were measured under TGF-β1 treatment and/or anti-integrin-β3 antibody by cell adhesion assay and wound healing assay.

Results: TGF-β1 had no effect on integrin-β1 mRNA expression. In the analysis of protein expression, TGF-β1 decreased the mature form of integrin-β1, but increased both the precursor form and core peptide of integrin-β1. The inhibitors of ERK and p38, but not Smad2/3, abrogated TGF-β1-induced changes in integrin-β1 protein expression. TGF-β1 increased integrin-β3 mRNA and protein levels. The inhibitors of Smad2/3, ERK and p38 attenuated the TGF-β1-induced increase in integrin-β3 mRNA and protein levels. Podocyte adhesion and migration were enhanced under the stimulation of TGF-β1. The blockade of interactions between integrin-αvβ3 and the extracellular matrix by the anti-integrin-β3 antibody abrogated the TGF-β1-induced enhancement in podocyte adhesion and migration.

Conclusions: Our results demonstrate that TGF-β1up-regulates integrin-β3 expression and down-regulates integrin-β1 expression through different pathways. The up-regulation of integrin-β3 expression enhances podocyte migration. This study provides a novel mechanism for TGF-β1 signaling in regulating podocyte migration.