Gene regulatory networks involved in activation of Notch signaling by AGEs in the pathogenesis of diabetic kidney disease

Diabetic kidney disease (DKD) is a progressive disease characterized by early events such as podocyte injury followed by glomerulosclerosis, varying degrees of proteinuria, decreased glomerular filtration rate, and eventual organ failure. Podocytes, essential for glomerular permselectivity, are targets for an array of noxious stimuli in diabetes. Notch signaling, critical for podocyte differentiation during nephrogenesis, reactivates in mature podocytes, as evidenced in DKD patients and animal models. Notch reactivation in adult podocytes implicated in de-differentiation and apoptosis. Although elevated advanced glycation end-products (AGEs), heterogeneous molecules derived from non-enzymatic glycation, were paralleled with Notch reactivation in podocytes, the precise mechanism remains unknown. This study identified a condensed network of 58 genes modulated by AGEs. These genes non-canonically reactivate Notch by suppressing the PI3K-AKT pathway and activating NF-kB signaling, affecting podocyte biology and function. The study provides novel information about reno-toxic events and new therapeutic targets to prevent podocyte injury and kidney dysfunction.