EFFICACY OF ANTIDIABETIC DRUGS IN NORMALIZING BLOOD PRESSURE IN HYPERTENSIVE DIABETIC ANIMALS AND NOVEL MECHANISMS IN THE DISTAL NEPHRON

Abstract

Hypertension associated diabetes is a highly prevalent disease and a major risk factor for DN, the most common cause of end stage renal disease in the US. The regulation of salt balance by the kidney is a major player for blood pressure regulation by adjusting blood volume in response to changes in systemic pressure. NCC and ENaC are expressed mainly in the late DCT and play a crucial role in blood pressure regulation. The cytoskeleton of eukaryotic cells provides structural support for the plasma membrane and regulates numerous epithelial transport proteins. Multiple antidiabetic drugs including, dapagliflozin and metformin, have shown a positive effect on the kidney. However, less is known about their mechanisms of action in terms of blood pressure regulation. The goals of this project are to define the mechanistic link between NCC and ENaC and the actin cytoskeleton proteins in the diabetic hypertensive db/db mice, furthermore, to investigate the effects of the antidiabetic agents including dapagliflozin and metformin on sodium reabsorption and blood pressure. We found that NCC interacts with the actin cytoskeleton filamin A and is dependent on CaMKII activity, which may serve as a feedback mechanism to maintain basal levels of NCC activity in the distal nephron. Moreover, we identified a novel blood pressure reducing role of metformin in diabetic nephropathy by regulating the cathepsin B-ENaC axis. Besides, we found the augmentation of cathepsin isoforms in the diabetic db/db mouse kidney is associated with an increase in renal MARCKS expression and proteolysis. On the other hand, NCC and the actin cytoskeleton linker protein ezrin interacts at the DCT in the hypertensive diabetic kidney. Dapagliflozin reduced NCC and ezrin interaction and alleviated blood pressure, blood glucose, urine osmolality, and promoted urinary sodium. Furthermore, some bioactive lipids in diabetic kidney membranes were altered after dapagliflozin treatment. Taken together, metformin and dapagliflozin may have the potential to normalize blood pressure in diabetics and reduce the risk of developing diabetic nephropathy.