The glucagon‐like peptide‐1 receptor agonist Exendin‐4, ameliorates contrast‐induced nephropathy through suppression of oxidative stress, vascular dysfunction and apoptosis independent of glycaemia

Abstract

Contrast-induced nephropathy (CIN) is a leading cause of hospital-acquired acute kidney injury, particularly in diabetic patients. Previous studies have shown renoprotective effects of glucagon-like peptide-1 (GLP-1) signalling; however, its role in CIN remains unexplored. This study investigates the prophylactic effect of exendin-4, a GLP-1R agonist, against CIN in a rat model mimicking both healthy and diabetic conditions. Animals were randomly divided into 7 groups: a control sham group (n = 8), and 2 identical sets of 3 disease groups, one received exendin-4 before exposure to contrast medium (CM), while the other served as untreated control. The 3 disease groups represented diabetes (n = 8), CIN (n = 8), or diabetes and CIN combined (n = 8). Untreated groups showed deteriorating renal function as indicated by significantly higher levels of serum creatinine and blood urea nitrogen, malondialdehyde, and endothelin-1 and caspase-3 expression compared to the sham control group. This was accompanied by a significant decrease in tissue reserves of reduced glutathione, superoxide dismutase, nitrate and endothelin nitric oxide synthase as well as deteriorating renal histology. The CM-induced changes in diabetic rats indicate impaired renal function, oxidative stress, vascular dysfunction, and apoptosis, and were significance higher in intensity compared to non-diabetic rats. Pretreatment with exendin-4 ameliorated all the aforementioned CM-induced nephropathic effects independent of the glycemic state. To our knowledge, this is the first study describing the prophylactic renoprotective effects of exendin-4 against CIN. With the current pharmaceutical use of exendin-4 as a hypoglycaemic agent, the GLP-1R agonist becomes an interesting candidate for human clinical trials on CIN prevention.

Contrast-induced nephropathy and oxidative stress: mechanistic insights for better interventional approaches

“…Other agents such as cardiotrophin-1 and antithrombin III, [ 53 , 54 ] exendin-4, [ 55 ] β-receptor antagonist, [ 56 , 57 ] phosphodiesterase-5 inhibitor, [ 58 – 61 ] an mTOR inhibitor, [ 62 ] exogenous sphingosylphosphorylcholine, [ 63 ] and sodium bicarbonate; [ 64 ] have been investigated in CIN models (Table 4 and Fig. 3 ).…”

Glycosylated Hemoglobin levels and the Risk for Contrast-Induced Nephropathy in Diabetic Patients Undergoing Coronary arteriography/Percutaneous Coronary Intervention

“…(10)The rat experiment showed that the CM-induced changes in diabetic rats indicate impaired renal function, oxidative stress, vascular dysfunction, and apoptosis, and were signi cance higher in intensity compared to non-diabetic rats. (26) Clinical studies have proven that for patients with known and unknown diabetes, elevated blood glucose levels before surgery are a powerful and independent risk factor for CIN. (27)However, preoperative blood glucose level can only indicate the current blood glucose status, and is affected by stress and recent diet, which makes it di cult to accurately predict the prognosis.…”

Resveratrol Protects Against Post-Contrast Acute Kidney Injury in Rabbits With Diabetic Nephropathy

“…Suggested mechanisms for the protective action of resveratrol on PC–AKI with DN based on observations by us and others are as follows: 1) We found that resveratrol alleviates impaired renal hypoxia observed in PC–AKI as shown by observing functional MRI R2 * parameters. 2) Resveratrol exerts a protective effect against contrast medium–induced injury by reducing oxidative stress and the excessive generation of reactive oxygen species (ROS) (Hussien et al, 2018). As reported, ROS may exert direct tubular and vascular endothelial injury, and further intensify renal parenchymal hypoxia by virtue of endothelial dysfunction and dysregulation of tubular transport (Andreucci et al, 2014).…”