Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel

Author:

Scindia Yogesh M.123,Gholam Mohammed F.45,Waleed Alina4,Liu Lauren P.4,Chacko Kevin M.4,Desai Dhruv1,Lopez Juliana Pena4,Malik Zeeshan4,Schramm Whitney C.4,Morales Angelica G.4,Carson-Marino Morgan46,Alli Abdel A.24

Affiliation:

1. Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA

2. Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA

3. Department of Pathology, University of Florida, Gainesville, FL 32610, USA

4. Department of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USA

5. Department of Basic Medical Sciences, College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia

6. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA

Abstract

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.

Funder

Vifor Pharma

U.S. National Institutes of Health (NIH) K01

NIH R01

Publisher

MDPI AG

Subject

General Biochemistry, Genetics and Molecular Biology,Medicine (miscellaneous)

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