Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel
Yogesh M. Scindia,
Mohammed F. Gholam,
Alina Waleed,
Lauren P. Liu,
Kevin M. Chacko,
Dhruv Desai,
Juliana Pena Lopez,
Zeeshan Malik,
Whitney C. Schramm,
Angelica G. Morales,
Morgan Carson-Marino,
Abdel A. Alli
Affiliations
Yogesh M. Scindia
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Mohammed F. Gholam
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Alina Waleed
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Lauren P. Liu
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Kevin M. Chacko
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Dhruv Desai
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Juliana Pena Lopez
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Zeeshan Malik
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Whitney C. Schramm
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Angelica G. Morales
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Morgan Carson-Marino
Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Abdel A. Alli
Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Diabetic nephropathy is the primary cause of morbidity in type 2 diabetes mellitus (T2DM) patients. New data indicate that hypertension, a common comorbidity in T2DM, can worsen outcomes of diabetic nephropathy. While metformin is a commonly prescribed drug for treating type 2 diabetes, its blood pressure regulating ability is not well documented. The aim of this study was to investigate the effect of metformin on normalizing blood pressure in salt-loaded hypertensive diabetic db/db mice. Sixteen-week-old male and female diabetic db/db mice were individually placed in metabolic cages and then randomized to a control vehicle (saline) or metformin treatment group. We evaluated the blood pressure reducing ability of metformin in salt-induced hypertension and progression of nephropathy in db/db mice. We observed that metformin- normalized systolic blood pressure in hypertensive diabetic mice. Mechanistically, metformin treatment reduced renal cathepsin B expression. Low cathepsin B expression was associated with reduced expression and activity of the epithelial sodium channel (ENaC), sodium retention, and thus control of hypertension. In addition, we identified that urinary extracellular vesicles (EVs) from the diabetic mice are enriched in cathepsin B. Compared to treatment with urinary EVs of vehicle-treated hypertensive diabetic mice, the amiloride-sensitive transepithelial current was significantly attenuated upon exposure of renal collecting duct cells to urinary EVs isolated from metformin-treated db/db mice or cathepsin B knockout mice. Collectively, our study identifies a novel blood pressure reducing role of metformin in diabetic nephropathy by regulating the cathepsin B-ENaC axis.
