PMID- 36830842
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240427
IS  - 2227-9059 (Print)
IS  - 2227-9059 (Electronic)
IS  - 2227-9059 (Linking)
VI  - 11
IP  - 2
DP  - 2023 Jan 21
TI  - Metformin Alleviates Diabetes-Associated Hypertension by Attenuating the Renal 
      Epithelial Sodium Channel.
LID - 10.3390/biomedicines11020305 [doi]
LID - 305
AB  - 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.
FAU - Scindia, Yogesh M
AU  - Scindia YM
AD  - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, 
      College of Medicine, University of Florida, Gainesville, FL 32610, USA.
AD  - Division of Nephrology, Hypertension and Renal Transplantation, Department of 
      Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
AD  - Department of Pathology, University of Florida, Gainesville, FL 32610, USA.
FAU - Gholam, Mohammed F
AU  - Gholam MF
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
AD  - Department of Basic Medical Sciences, College of Medicine, King Saud bin 
      Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia.
FAU - Waleed, Alina
AU  - Waleed A
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Liu, Lauren P
AU  - Liu LP
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Chacko, Kevin M
AU  - Chacko KM
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Desai, Dhruv
AU  - Desai D
AD  - Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, 
      College of Medicine, University of Florida, Gainesville, FL 32610, USA.
FAU - Lopez, Juliana Pena
AU  - Lopez JP
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Malik, Zeeshan
AU  - Malik Z
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Schramm, Whitney C
AU  - Schramm WC
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Morales, Angelica G
AU  - Morales AG
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Carson-Marino, Morgan
AU  - Carson-Marino M
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
AD  - Department of Pharmaceutics, College of Pharmacy, University of Florida, 
      Gainesville, FL 32610, USA.
FAU - Alli, Abdel A
AU  - Alli AA
AD  - Division of Nephrology, Hypertension and Renal Transplantation, Department of 
      Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
AD  - Department of Physiology and Aging, College of Medicine, University of Florida, 
      Gainesville, FL 32610, USA.
LA  - eng
GR  - K01 DK099617/DK/NIDDK NIH HHS/United States
GR  - R01 DK123078/DK/NIDDK NIH HHS/United States
GR  - DK099617/NH/NIH HHS/United States
GR  - DK123078-01A1/NH/NIH HHS/United States
PT  - Journal Article
DEP - 20230121
PL  - Switzerland
TA  - Biomedicines
JT  - Biomedicines
JID - 101691304
PMC - PMC9953274
OTO - NOTNLM
OT  - ENaC
OT  - cathepsin B
OT  - diabetes
OT  - hypertension
COIS- The authors declare no conflict of interest.
EDAT- 2023/02/26 06:00
MHDA- 2023/02/26 06:01
PMCR- 2023/01/21
CRDT- 2023/02/25 01:26
PHST- 2022/12/30 00:00 [received]
PHST- 2023/01/14 00:00 [revised]
PHST- 2023/01/17 00:00 [accepted]
PHST- 2023/02/25 01:26 [entrez]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/02/26 06:01 [medline]
PHST- 2023/01/21 00:00 [pmc-release]
AID - biomedicines11020305 [pii]
AID - biomedicines-11-00305 [pii]
AID - 10.3390/biomedicines11020305 [doi]
PST - epublish
SO  - Biomedicines. 2023 Jan 21;11(2):305. doi: 10.3390/biomedicines11020305.