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

Abstract

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.

Metformin Reverses the Effects of Angiotensin 2 in Human Mammary Arteries by Modulating the Expression of Nitric Oxide Synthases

“…As regarding the inducible NO synthase, the drug has been reported to negatively regulate the iNOS expression in vascular smooth muscle cells treated with TNFα (28). In a very recent data, Dawood et al demonstrated the activation of renal artery angiotensin 1 receptor, upregulation of endothelin-1 and iNOS, as well as downregulation of eNOS in a rat model of diabetic nephropathy, effects that were reversed by Metf (29).…”

Morphological changes in the kidney tissue of rats with experimental diabetes mellitus and during correction with metformin and modulators of hydrogen sulfide metabolism

“…Препаратом першої лінії у лікуванні ЦД 2 типу з доведеними нефропротекторними властивості є цукрознижуючий засіб метформін. Показано, що захисна дія метформіну на нирки реалізується через різноманітні механізми, а саме зменшення глікозилування білків, посилення аутофагії, зниження активності запалення, оксидативного стресу, фіброгенезу та апоптозу [1,2,6,7]. У той же час практично відсутня інформація щодо ролі системи H 2 S у реалізації нефропротекторної дії метформіну.…”

“…За цих умов застосування метформіну виявляє нефропротекторну активність, яка характеризується зменшенням виразності нефросклерозу, гіпертрофії ниркових тілець, деструкції ендотелію, інтерстиційного запалення та пошкодження тубулярного апарату. Виявлені нами гістологічні зміни на тлі застосування метформіну не суперечать даним літератури при проведенні подібних досліджень [2,7].…”

Metformin Suppresses Thioacetamide-Induced Chronic Kidney Disease in Association with the Upregulation of AMPK and Downregulation of Oxidative Stress and Inflammation as Well as Dyslipidemia and Hypertension

“…Metformin induced ovulation in nonobese women with PCOS better than the first-line drug for anovulatory infertility treatment, clomiphene [ 16 ]; (ii) metformin is widely used in clinical and research studies for cardiovascular and liver protection [ 17 , 18 ]. Metformin has been suggested to reduce body weight, inhibit the deposition of fats in blood vessels (atherosclerosis), improve hemostatic function and immune cell performance, and protect against nonalcoholic steatohepatitis-induced hepatocellular carcinoma [ 17 , 18 ]; (iii) metformin also prevents apoptosis and cellular deterioration with age (senescence) in intervertebral disc degeneration via autophagy stimulation through the activation of AMPK, which ameliorate the degeneration of discs in vivo [ 19 ]; and (iv) metformin ameliorates several types of kidney diseases such as autosomal dominant polycystic kidney disease and acute kidney injury; reduces mortality in patients with CKD, diabetic nephropathy [ 20 , 21 ], and gentamicin-induced nephrotoxicity via reducing mitochondrial ROS and hence improves mitochondrial homeostasis [ 22 ] in patients with stable chronic renal impairment [ 23 ]; and, finally, metformin was reported to decrease the risk of death in patients with kidney cancers and localized and metastatic renal cell carcinoma [ 24 ]. Therefore, this study examined if metformin can protect against TAA-induced kidney injury and fibrosis in rats using physiological and biochemical methods, basic and special histology staining, immunoblotting, and real-time PCR (to assess the relative gene expression) to test the proposed working hypothesis.…”