The Effect of Metformin in Diabetic and Non-Diabetic Rats with Experimentally-Induced Chronic Kidney Disease

Abstract

This work aimed to investigate whether treatment with the antidiabetic drug metformin would affect adenine-induced chronic kidney disease (CKD) in non-diabetic rats and rats with streptozotocin (STZ)-induced diabetes. Rats were randomly divided into eight groups, and given either normal feed, or feed mixed with adenine (0.25% w/w, for five weeks) to induce CKD. Some of these groups were also simultaneously treated orally with metformin (200 mg/kg/day). Rats given adenine showed the typical signs of CKD that included detrimental changes in several physiological and traditional and novel biochemical biomarkers in plasma urine and kidney homogenates such as albumin/creatinine ratio, N-acetyl-beta-D-glucosaminidase, neutrophil gelatinase-associated lipocalin, 8-isoprostane, adiponectin, cystatin C, as well as plasma urea, creatinine, uric acid, indoxyl sulfate, calcium, and phosphorus. Several indices of inflammation and oxidative stress, and renal nuclear factor-κB and nuclear factor erythroid 2-related factor 2 levels were also measured. Histopathologically, adenine caused renal tubular necrosis and fibrosis. The activation of the intracellular mitogen-activated protein kinase signaling pathway was inhibited in the groups that received metformin and STZ together, with or without adenine induced-CKD. Induction of diabetes worsened most of the actions induced by adenine. Metformin significantly ameliorated the renal actions induced by adenine and STZ when these were given singly, and more so when given together. The results suggest that metformin can be a useful drug in attenuating the progression of CKD in both diabetic and non-diabetic rats.

Catalpol Attenuates Oxidative Stress and Inflammation via Mechanisms Involving Sirtuin-1 Activation and NF-κB Inhibition in Experimentally-Induced Chronic Kidney Disease

“…The overproduction of ROS and the inadequate response of antioxidants play an important role in the pathogenesis of CKD, both clinically and experimentally [ 14 , 32 , 36 , 54 ]. Due to its reactivity to lipids, ROS oxidize the lipids from cell membranes, causing lipid peroxidation, which eventually leads to the formation of reactive aldehydes, namely MDA, a bioactive marker that was measured in our study [ 36 , 54 ].…”

“…Then, they were sectioned into 4 µm pieces using a microtome from Leica Biosystems (Nussloch, Germany) and mounted onto slides. The slides were stained with hematoxylin and eosin (H&E) to assess acute tubular necrosis, Sirius red stain to evaluate interstitial fibrosis, and periodic acid Schiff (PAS) stain to assess the glomerular integrity [ 32 , 33 ]. The stained sections were blindly evaluated under a light microscope by a pathologist.…”

“…A score of 0 was given to a slide that exhibited normal kidney architecture with no tubular injury, a score of 1 for tissues that had less than 25% tubular injury, 2 for tissues with tubular injury of 26–50%, 3 for 51–75%, and a score of 4 was given to tissues with more than 75% of necrotic tubular injury. The proportion of red-stained fibrotic area in the cortex of each section, stained with Sirius red stain, was graded semi-quantitatively and the fibrosis index was calculated and expressed in percentage according to the protocol previously reported [ 32 , 34 ].…”

IRW (Isoleucine–Arginine–Tryptophan) Improves Glucose Tolerance in High Fat Diet Fed C57BL/6 Mice via Activation of Insulin Signaling and AMPK Pathways in Skeletal Muscle

“…For example, AdipoRon, a small-molecule agonist of adiponectin receptor is used at 50 mg/kg BW [ 29 ], curcumin at 100 mg/kg BW [ 30 ], soy β-Conglycin at 10% of diet ( w / w ) [ 31 ] and the di-peptide (Trp-His) at dosages ranging between 10–100 mg/kg BW [ 32 , 33 ]. Moreover, metformin is used at 200 mg/kg BW in rodent models of diabetes [ 34 , 35 ].…”

Recent Progress in the Diagnosis and Management of Type 2 Diabetes Mellitus in the Era of COVID-19 and Single Cell Multi-Omics Technologies

“…The authors speculate that the underlying mechanism of this renoprotective effect may be associated with glycemic control, lipid metabolism, and anti-oxidative and anti-inflammatory functions [ 69 ]. Al Za’abi et al found that metformin can be a useful drug in attenuating the progression of adenine-induced CKD in both diabetic and non-diabetic rats [ 70 ]. Increasing numbers of studies are investigating whether metformin exerts its hypoglycemic effect through the modulation of microbiome in the diabetic rat gut [ 71 ].…”