Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel
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 pr...
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| Format: | Article |
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MDPI AG
2023-01-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/2/305 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Yogesh M. Scindia |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T09:07:02Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-11T09:07:02Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-7fcb29cb8c8f465bab7cddaaa2531bef2023-11-16T19:16:14ZengMDPI AGBiomedicines2227-90592023-01-0111230510.3390/biomedicines11020305Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium ChannelYogesh M. Scindia0Mohammed F. Gholam1Alina Waleed2Lauren P. Liu3Kevin M. Chacko4Dhruv Desai5Juliana Pena Lopez6Zeeshan Malik7Whitney C. Schramm8Angelica G. Morales9Morgan Carson-Marino10Abdel A. Alli11Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADivision of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADepartment of Physiology and Aging, College of Medicine, University of Florida, Gainesville, FL 32610, USADivision of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USADiabetic 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.https://www.mdpi.com/2227-9059/11/2/305diabeteshypertensionENaCcathepsin B |
| spellingShingle | 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 Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel Biomedicines diabetes hypertension ENaC cathepsin B |
| title | Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel |
| title_full | Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel |
| title_fullStr | Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel |
| title_full_unstemmed | Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel |
| title_short | Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal Epithelial Sodium Channel |
| title_sort | metformin alleviates diabetes associated hypertension by attenuating the renal epithelial sodium channel |
| topic | diabetes hypertension ENaC cathepsin B |
| url | https://www.mdpi.com/2227-9059/11/2/305 |
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