Drug Targets for Oxidative Podocyte Injury in Diabetic Nephropathy

Abstract

Diabetic nephropathy (DN) is one the most prevalent chronic complications of diabetes mellitus that affects as much as one-third of diabetic patients irrespective of the type of diabetes. Hyperglycemia is the key trigger for DN that initiates a number of microscopic and ultramicroscopic changes in kidney architecture. Microscopic changes include thickening of the glomerular basement membrane (GBM), tubular basement membrane (TBM), mesangial proliferation, arteriosclerosis, and glomerulotubular junction abnormalities (GTJA). Among the ultramicroscopic changes, effacement of podocytes and decrease in their density seem to be the centerpiece of DN pathogenesis. These changes in kidney architecture then produce functional deficits, such as microalbuminuria and decreased glomerular filtration rate (GFR). Among several mechanisms involved in inflicting damage to podocytes, injuries sustained by increased oxidative stress turns out to be the most important mechanism. Different variables that are included in increased production of reactive oxygen species (ROS) include a hyperglycemia-induced reduction in glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation via hyperglycemia, advanced glycation end products (AGEs), protein kinase C (PKC), and renin-angiotensin-aldosterone system (RAAS). Unfortunately, control of podocyte injury hasn't received much attention as a treatment approach for DN. Therefore, this review article is mainly concerned with the exploration of various treatment options that might help in decreasing the podocyte injury, mainly by reducing the level of NADPH oxidase-mediated generation of ROS. This article concludes with a view that certain NADPH oxidase inhibitors, RAAS inhibitors, statins, antidiabetic drugs, and antioxidant vitamins might be useful in decreasing podocyte injury and resultant structural and functional kidney impairments in DN.

Keywords: diabetes; diabetic nephropathy; hyperglycemia; oxidative podocyte injury; oxidative stress.

Figure 1. Prevalence of Diabetes. Figure adapted from the diabetes atlas published by International Diabetes Federation (IDF).

Retrieved from IDF website on November 12, 2015: http://www.idf.org/sites/default/files/Atlas-poster-2014_EN.pdf

Figure 2. Mechanism of increase in oxidative stress and resultant podocyte injury due to hyperglycemia.

High glucose gets metabolized to form obnoxious glucose metabolites; directly reduces the quantity of antioxidants like glutathione (GSH); fuses with proteins to form advanced glycation end products (AGEs); induces protein kinase C (PKC) signaling and deranges renin-angiotensin-aldosterone system (RAAS). All these mechanism tend to increase oxidative stress by inducing the action of NADPH oxidase. The reactive oxygen species (ROS), thus produced, inflict injury to podocytes and decrease their density.