Effects of empagliflozin and tempol combined therapy on NRF-2 pathway in experimental gestational diabetic nephropathy

Diabetes mellitus (DM) is a metabolic diseases characterized by chronic hyperglycemia due to impaired insulin secretion, insulin resistance, or both. There are two main types of diabetes. Type 1 diabetes (T1D) is an autoimmune disease that causes destruction of pancreatic beta cells. Type 2 diabetes (T2D), which is much more common, occurs primarily as a result of gradual disruption of glucose regulation due to the combination of dysfunctional pancreatic beta cells and insulin resistance. Gestational diabetes mellitus (GDM) is associated with T2D. However, pathological pregnancies, including GDM, are associated with high levels of oxidative stress due to both overproduction of free radicals and disruptions in antioxidant defense. In the long run, T2D causes an increased incidence of diabetic nephropathy (DN). DN is one of the leading causes of end-stage renal disease; kidney damage due to DN is largely attributed to increased oxidative stress, which affects metabolic activity and hemodynamic pathways. Nrf2 (nuclear factor erythroid 2 associated factor 2) is an important regulator of genes associated with antioxidant response, biotransformation of endobiotics and xenobiotics, lipid and carbohydrate metabolism, cellular iron homeostasis, autophagy, and inflammation. Nrf2 is a redox sensitive transcription factor and controls the production of many antioxidant enzymes and phase II detoxification enzymes. Activation of Nrf2 signaling has an important role in preventing peripheral complications of diabetes. Since Nrf2 is the main regulator of antioxidant responses, its role in kidney diseases has become one of the most interesting areas of study. Sodium-glucose cotransporter-2 (SGLT2) proteins are expressed in the proximal convoluted tubule of the kidneys. These transporters are an ideal target for diabetes treatment because they are responsible for 90% of filtered glucose reabsorption. Pharmacological inhibition of SGLT2 co-transporters reduces hyperglycemia by lowering the renal glucose threshold and increasing urinary glucose excretion. Nrf2 is also known to participate in glucose regulation and binding sequences found in the SGLT2 promoter. In this case, understanding and evaluating the relationship between SGLT2 and NRF2 through its antioxidative effect will provide a new perspective on SGLT2 activation in diabetic pathophysiology. Tempol is an effective low molecular weight antioxidant with superoxide dismutase (SOD)-mimic activity. The available information on the effect of Tempol therapy on the progression of chronic kidney disease is partial. Tempol is also known to be a protective antioxidant against ischemic injury in many animal models. However, there are limited studies on the protective effect of Tempol on kidney pathophysiology. In the light of all this information, in this study, it is aimed to evaluate the antioxidant effects of the SGLT2 inhibitor Empagliflozin and Tempol, separately and in combination, through the regulation of NRF-2 in renal tubular cells.