Targeting signaling pathways in glomerular diseases

Abstract

Podocytes are highly specialized epithelial cells that line the urinary surface of the glomerular capillary tuft. Dysfunction or death of podocytes impacts glomerular permeability and filtration. Here, we discuss the recent findings about the role of specific cell signaling pathways in glomerular diseases with an emphasis on the molecules in the podocyte that represent candidate therapeutic targets. A number of local endogenous factors that retard the progression of diabetic nephropathy have recently been identified and include angiopoietin-1 (Angpt1), Smad7 and nuclear factor (erythroid-derived 2)-like 2 (Nrf2). Calcium-dependent regulation of podocyte actin dynamics involving transient receptor potential canonical (TRPC) channels and the Rho and Rac small GTPases has been shown to play important functions in glomerular health and disease. A central role for mammalian target of rapamycin (mTOR) activation in the development of diabetic nephropathy and regulation of autophagic flux in podocytes during aging has been demonstrated. Discovery of a circulating factor (suPAR) that can modulate outside-in beta3 integrin signaling in recurrent focal segmental glomerulosclerosis provides exciting therapeutic possibilities. Another secreted factor, the hyposialylated form of angiopoietin-like-protein 4 (ANGPTL4) was found to favor albuminuria in rats and in minimal change disease. Therapeutic sialylation of ANGPTL4 could limit albuminuria. Finally, neutralization of de novo paracrine activation of glomerular epithelial cells by heparin-binding epidermal growth factor (EGF)-like growth factor or EGF receptor antagonists could limit crescent formation and renal failure in immune-mediated vasculitis. Here, we review the recent developments in our understanding of signaling pathways required for podocyte function in health and disease. Manipulation of these pathways provides an attractive therapeutic option for glomerular diseases.