Potential Novel Therapeutic Approaches in Managing Diabetic Nephropathy

Abstract

Diabetes, also known as diabetes mellitus (DM), is a group of metabolic disorders characterized by chronic hyperglycemia due to defects in insulin secretion, insulin action, or both. It is associated with several complications that are classified as microvascular and macrovascular complications. Diabetic nephropathy (DN) also known as diabetic kidney disease (DKD), a common diabetic microvascular complication, is characterized by macro albuminuria, hypertension, and decreased glomerular filtration rate (GFR). It is the leading cause of morbidity and end-stage renal disease, affecting approximately 30% of type 1 and 40% of type 2 diabetic patients. Although huge advancements have been accomplished in tight glycemic control and blood pressure control, they are still unable to prevent the progression of DKD. Hence it is a matter of urgency to develop novel therapeutic drugs for the management of diabetes and its complications. A recent study has reported the synthesis of novel series of carbocyclic acylhydrazone derivatives of uracil, thymine, and cytosine from the corresponding nucleic bases and their biological activity to treat diabetic nephropathy. The study investigated the combinatorial effect of the acylhydrazone and nucleic base groups in a series of pyramidal acylhydrazone derivatives as they possess a wide range of biological activities for diabetic therapy. Among these compounds, the carbocyclic derivative of uridyl acylhydrazones “5a” showed promising effects in the suppression of glomerular mesangial cell proliferation and matrix protein accumulation through ROS-dependent mechanism after testing it on cultured rat mesangial cells. Furthermore, several studies have highlighted the major role of ROS in the onset and progression of diabetic nephropathy. Hence, in this study, we aim to investigate the effect of drug “5a” on the production of NADPH oxidase 4 (NOX-4), one of the main sources of ROS. We hypothesize that drug “5a” could attenuate DKD in mice with type 2 diabetes by targeting NOX4-dependent pathways.