Project 465229

High blood sugar and high blood pressure are major risk factors in the development of heart and kidney diseases, including stroke, heart attacks and kidney failure. In the kidney, blood passes through the kidney filters (glomeruli) and then into kidney tubules, where many components are reabsorbed back into the body. Among such substances, 90% of glucose is reabsorbed back by glucose transporters. Keeping blood sugar at normal levels with insulin or through inhibitors of a glucose transporter called the sodium-glucose cotransporter-2 (SGLT2) is the best way to ameliorate or forestall complications in people with diabetes. However, the way in which SGLT2 inhibitors work and how their levels in diabetes are controlled are not well understood. We (Dr. John Chan's group) reported that a protein called "nuclear factor erythroid 2-related factor 2 (NRF2)" when overexpressed specifically in the kidney of type 1 diabetic (T1D) mice with general body deletion (knockout) of NRF2 increases blood glucose, blood pressure and the expression of SGLT2. We are now examining whether the removal of NRF2 specifically from the kidney decreases blood sugar levels, blood pressure and kidney damage in mouse models with type 2 diabetes (T2D). We will use the state-of-art genetic methodology to remove this protein (NRF2) from the kidney in two in vivo models of T2D --genetic obese and high-fat diet-induced T2D mouse models-and in vitro in cultured human kidney cells. Our studies will show whether genetic removal of NRF2 solely in the kidney will prevent the effect of high glucose and free fatty acid on SGLT2 expression and the development of kidney complications in vivo and in vitro. Our research will help the clinicians to understand how NRF2 activation affects blood glucose, blood pressure and kidney failure in patients with diabetes and will improve clinical treatment for diabetics.