Effects of Angiotensin Receptor Blocker on Oxidative Stress and Cardio-Renal Function in Streptozotocin-Induced Diabetic Rats

Abstract

It is becoming increasingly evident that cumulative oxidative stress has a very close relationship with the progression of many human diseases such as diabetes mellitus (DM), cardiovascular diseases, and cancer.1) It has also been shown that oxidative stress may play a role in the pathogenesis of diabetic complications such as cardiomyopathy and nephropathy.2,3) Hyperglycemia can induce increased production of reactive oxygen metabolites and species. Elevated glucose concentrations may also increase the levels of oxygen radicalscavenging enzymes in cultured endothelial cells 4) and the kidney of rats with streptozotocin (STZ)-induced diabetes. 5)An imbalance between reactive oxygen species (ROS) generation and antioxidant capacity favoring the former leads to oxidative stress and oxidative damage. Most vascular ROS are produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, a multisubunit enzyme that catalyzes O 2 Ϫ production. Activation of NADPH oxidase, autooxidation of glucose, and the formation of advanced glycation end products seem to be relevant to the elevated oxidative stress in diabetes. NADPH oxidase consists of membrane-associated subunits (gp91 phox and p22 phox ) and cytosolic subunits (p47 phox , p40 phox , p67 phox , and Rac).6) Nox4 was identified initially as a kidney NADPH oxidase and recent studies have shown that Nox4 is also abundant in vascular cells, especially endothelial cells, and is implicated in vascular pathologies. An elevation in angiotensin II (Ang II) levels is a frequent occurrence in a diverse number of cardio-and reno-vascular diseases. An important effect of Ang II is the activation of NADPH oxidase, a major source of ROS production by vascular cells. 7) Inhibition of the Ang II type I receptor (AT-1R) by angiotensin receptor blockers (ARB) in some studies of experimental animals showed that this ARB reduces activities of oxidases and completely prevents the increase in NADPH oxidase activity caused by Ang II. [8][9][10][11] Oxidative stress also plays a key role in the development of hypertrophy in diabetic conditions. It has been studied extensively that transforming growth factor-b1 (TGF-b1) as a mediator of a hypertrophic and prosclerotic changes in diabetic diseases.12,13) Ang II may induce myocardial fibrosis and thickening of the vessel wall in hypertension by increasing the production of TGF-b1. The circulating levels of TGF-b1 are increased in patients with diabetic nephropathy and reduced progression of this complication during treatment with angiotensin-converting enzyme inhibitors (ACEI) is associated with reduced levels of TGF-b1.14) Although the understanding of how hyperglycemia-induced oxidative stress ultimately leads to tissue damage has advanced considerably in recent years, 15) effective therapeutic strategies to prevent or delay the development of this damage remain limited.16) The present study investigated the effect of an ARB, losartan, on cardio-renal function, fibrosis, and oxidative stress-related factors such as protein expressio...

Protective effect of magnesium on renal function in STZ-induced diabetic rats

“…Renet et al, showed that marked increase in the KW/BW, tubulointerstitial fibrosis and fibronectin in STZ-induced diabetic rats from 8 to 16 weeks [57]. Arozal et al, oxidative stress is associated with development of hypertrophy in diabetes [58]. Sharma et al, revealed that renal hypertrophy in T1D was related to overexpression of TGF-β1 in the glomerular mesangial cells [59].…”

Effect of telmisartan on the expression of adiponectin receptors and nicotinamide adenine dinucleotide phosphate oxidase in the heart and aorta in type 2 diabetic rats

“…NADPH oxidase has emerged as the main source of ROS in the cardiovascular tissues [44]. It was reported that the expression of NADPH oxidase subunits, p22phox and Nox4 was significantly increased in the heart of diabetic mice and rats [13,14,45,46], indicating that Nox4 was an important source of ROS in the left ventricle and Nox4-derived ROS contribute to cardiomyopathy at early stages of type 1 diabetes [45]. Consistent with these studies, the present study also showed that the expression of myocardial p22phox and Nox4 was significantly increased in type 2 diabetic rats, suggesting that NADPH oxidase might play a crucial role in the development of diabetic cardiomyopathy.…”

Oxidant Mechanisms in Renal Injury and Disease

“…Despite some adverse side effects that sometimes occur with the application of these agents to CKD patients, they are overall effective in improving kidney function and proteinuria. All of these AT1 blockers have been shown to reduce oxidative stress in the kidneys during disease and injury (145,212,267), with losartan downregulating expression of NADPH oxidase (9). and lipid peroxidation as second messengers.…”