Insulin controls cytoskeleton reorganization and filtration barrier permeability via the PKGIα-Rac1-RhoA crosstalk in cultured rat podocytes

Abstract

Podocyte foot processes are an important cellular layer of the glomerular barrier that regulates glomerular permeability. Insulin via the protein kinase G type Iα (PKGIα) signaling pathway regulates the balance between contractility and relaxation (permeability) of the podocyte barrier by regulation of the actin cytoskeleton. This mechanism was shown to be disrupted in diabetes. Rho family guanosine-5′-triphosphates (GTPases) are dynamic modulators of the actin cytoskeleton and expressed in cells that form the glomerular filtration barrier. Thus, changes in Rho GTPase activity may affect glomerular permeability to albumin. The present study showed that Rho family GTPases control podocyte migration and permeability. Moreover these processes are regulated by insulin in PKGIα-dependent manner. Modulation of the PKGI-dependent activity of Rac1 and RhoA GTPases with inhibitors or small-interfering RNA impair glomerular permeability to albumin. We also demonstrated this mechanism in obese, insulin-resistant Zucker rats. We propose that PKGIα-Rac1-RhoA crosstalk is necessary in proper organization of the podocyte cytoskeleton and consequently the stabilization of glomerular architecture and regulation of filtration barrier permeability.