The Role of PKGI alpha and AMPK Signaling Interplay in the Regulation of Albumin Permeability in Cultured Rat Podocytes

The permeability of the glomerular filtration barrier (GFB) is mainly regulated by podocytes and their foot processes. Protein kinase G type I alpha (PKGI alpha) and adenosine monophosphate-dependent kinase (AMPK) affect the contractile apparatus of podocytes and influence the permeability of the GFB. Therefore, we studied the interplay between PKGI alpha and AMPK in cultured rat podocytes. The glomerular permeability to albumin and transmembrane FITC-albumin flux decreased in the presence of AMPK activators and increased in the presence of PKG activators. The knockdown of PKGI alpha or AMPK with small-interfering RNA (siRNA) revealed a mutual interaction between PKGI alpha and AMPK and influenced podocyte permeability to albumin. Moreover, PKGI alpha siRNA activated the AMPK-dependent signaling pathway. AMPK alpha 2 siRNA increased basal levels of phosphorylated myosin phosphate target subunit 1 and decreased the phosphorylation of myosin light chain 2. Podocytes that were treated with AMPK or PKG activators were characterized by the different organization of actin filaments within the cell. Our findings suggest that mutual interactions between PKGI alpha and AMPK alpha 2 regulate the contractile apparatus and permeability of the podocyte monolayer to albumin. Understanding this newly identified molecular mechanism in podocytes provides further insights into the pathogenesis of glomerular disease and novel therapeutic targets for glomerulopathies.