Metformin Is Associated with the Inhibition of Renal Artery AT1R/ET-1/iNOS Axis in a Rat Model of Diabetic Nephropathy with Suppression of Inflammation and Oxidative Stress and Kidney Injury
Amal F. Dawood,
Amro Maarouf,
Norah M. Alzamil,
Maha A. Momenah,
Ayed A. Shati,
Nervana M. Bayoumy,
Samaa S. Kamar,
Mohamed A. Haidara,
Asmaa M. ShamsEldeen,
Hanaa Z. Yassin,
Peter W. Hewett,
Bahjat Al-Ani
Affiliations
Amal F. Dawood
Department of Basic Medical Sciences, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
Amro Maarouf
Department of Clinical Biochemistry, Birmingham Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham B9 5SS, UK
Norah M. Alzamil
Department of Clinical Science, Family Medicine, College of Medicine, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
Maha A. Momenah
Department of Biology, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh 11671, Saudi Arabia
Ayed A. Shati
Department of Child Health, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
Nervana M. Bayoumy
Department of Physiology, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
Samaa S. Kamar
Department of Histology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
Mohamed A. Haidara
Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
Asmaa M. ShamsEldeen
Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
Hanaa Z. Yassin
Department of Physiology, Kasr Al-Aini Faculty of Medicine, Cairo University, Cairo 12613, Egypt
Peter W. Hewett
Institute of Cardiovascular Sciences, College of Medicine and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
Bahjat Al-Ani
Department of Physiology, College of Medicine, King Khalid University, Abha 62529, Saudi Arabia
Diabetes is the most common cause of end-stage renal disease, also called kidney failure. The link between the renal artery receptor angiotensin II type I (AT1R) and endothelin-1 (ET-1), involved in vasoconstriction, oxidative stress, inflammation and kidney fibrosis (collagen) in diabetes-induced nephropathy with and without metformin incorporation has not been previously studied. Diabetes (type 2) was induced in rats and another group started metformin (200 mg/kg) treatment 2 weeks prior to the induction of diabetes and continued on metformin until being culled at week 12. Diabetes significantly (p < 0.0001) modulated renal artery tissue levels of AT1R, ET-1, inducible nitric oxide synthase (iNOS), endothelial NOS (eNOS), and the advanced glycation end products that were protected by metformin. In addition, diabetes-induced inflammation, oxidative stress, hypertension, ketonuria, mesangial matrix expansion, and kidney collagen were significantly reduced by metformin. A significant correlation between the AT1R/ET-1/iNOS axis, inflammation, fibrosis and glycemia was observed. Thus, diabetes is associated with the augmentation of the renal artery AT1R/ET-1/iNOS axis as well as renal injury and hypertension while being protected by metformin.
