The Role of SGLT2 Inhibitors and DPP4 Inhibitors in Preventing Diabetic Nephropathy

Abstract

Diabetic nephropathy is the most common cause of end stage kidney disease in the world. Newer diabetic medications have arrived over the last few years. However there is lack of experimental and clinical evidence in favour of better outcomes. The two most important drug categories that have emerged in this century are the dipeptidyl peptidase-4 inhibitors DPP4 inhibitors (DPP4i) and sodium glucose cotransporter inhibitors (SGLT2i). Their role in preventing diabetic nephropathy irrespective of their glycaemic benefits is unknown. The aim of our project was to demonstrate the renoprotective benefits of these medications. In this thesis we used endothelial nitric oxide synthase knock out (eNOS -/-) mice and induced type 1 diabetes using streptozotocin (STZ) injection. We studied the changes of diabetic nephropathy in these mice including clinical outcomes, biochemical changes, inflammatory and fibrotic pathways. Our study with empagliflozin showed that SGLT2 inhibitors might not have a beneficial role in preventing diabetic nephropathy when blood glucose levels were high. We studied the role of linagliptin, a DPP4i, in preventing the interaction between DPP4 and cation independent mannose-6-phosphate receptor (CIM6PR) in the setting of high glucose in an in vitro model using kidney proximal tubular cells. Our results showed that linagliptin reduced the interaction between DPP4 and CIM6PR possibly resulting in the prevention of activation of latent TGFß. We proved this subsequently in an in vivo model of STZ induced type 1diabetes in eNOS -/- mice using linagliptin and another DPP4i, saxagliptin. We demonstrated that these DPP4i were able to reduce tubulointerstitial fibronectin deposition and demonstrated reduced expression of pSmad2/3, a downstream marker of TGFß activation. Hence our studies have helped in partly identifying the puzzle of diabetic nephropathy and provide some answers on the role of newer anti diabetic agents in preventing it.