Diltiazem Attenuates Oxidative Stress in Diabetic Rats

Abstract

Diabetic nephropathy is the main cause of end stage renal damage. Oxidative stress is involved in the etiology of diabetic nephropathy and intracellular calcium is reported to play a considerable role in the development of renal damage in the diabetic kidney. Calcium antagonism can slow the progression of renal impairment in diabetes. The present study was thus designed to examine the effect of a nondihydropyridine calcium channel blocker, diltiazem, on renal function, oxidative stress, and nitric oxide (NO) release in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced by a single intraperitoneal injection of STZ (65 mg/kg) in rats. After 4 weeks of STZ injection, the rats were divided in to four groups: control rats, diabetic rats treated with saline, and two groups of diabetic rats treated with diltiazem (5 and 10 mg/kg, i.p, respectively) for 8 weeks starting from 4 weeks after STZ injection. Renal function was assessed by creatinine, blood urea nitrogen, creatinine clearance, and urea clearance. Oxidative stress was measured by renal malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD), and catalase. We also measured renal nitrite levels. At the end of the 8 weeks, diabetic rats exhibited renal dysfunction as evidenced by reduced creatinine and urea clearance along with enhanced albumin excretion rate as compared with control rats. Biochemical analysis of kidneys revealed a marked increase in oxidative stress demonstrated by increased lipid peroxidation and decreased activities of key antioxidant enzymes, GSH, SOD, and catalase in diabetic rats. Release of NO also significantly higher in diabetic rats than controls. Chronic treatment with diltiazem in diabetic rats significantly attenuated both renal dysfunction and oxidative stress along with increased NO levels as compared with untreated diabetic rats. The kidneys of diabetic rats showed morphological changes such as hyaline casts, glomerular thickening, and moderate interstitial fibrosis and arteriolopathy, whereas diltiazem administration markedly prevented diabetic-induced renal morphological alterations. The present study suggests that oxidative stress/nitrosative stress is increased in the diabetic kidney and calcium channel blockage can prevent these changes. The results also suggest that in STZinduced diabetic rats, the protective action of diltiazem might be mediated, at least in part, by its effect on tissue oxidant/ antioxidant status.

Endothelin A Receptor Blockade Reduces Diabetic Renal Injury via an Anti-Inflammatory Mechanism

“…ABT-627 treatment of sham rats also decreased ED-1-positive cells in the renal cortex; however, it is not clear whether the mechanism is similar in sham and hyperglycemic rats. Although renal hypertrophy was evident in HG rats, we did not observe significant structural changes in the kidney during this study, although some previous reports have shown glomerular enlargement, matrix expansion, interstitial fibrosis, and arteriolopathy during early diabetes in the STZ model (33)(34)(35)(36). These differences may be due to the strain or gender of rats used or the use of insulin to maintain moderate hyperglycemia.…”

Repurposing Diltiazem for Its Neuroprotective Anti-Dementia Role against Intra-Cerebroventricular Streptozotocin-Induced Sporadic Alzheimer’s Disease-Type Rat Model

“…ICV-STZ-induced rats exhibited an increase in LPO as measured by TBARS levels and decreased the GSH and SOD levels significantly. DTZ at 10, 20, and 40 mg/kg dose-dependently restored the altered enzyme status, which agreed with earlier studies that DTZ significantly attenuated oxidative stress in STZ-induced diabetic rabbits and aluminum chloride-induced oxidative stress in mice [29,64].…”

The effects of grape seed on apoptosis-related gene expression and oxidative stress in streptozotocin-induced diabetic rats

“…17,18,22 High serum glucose levels promote the oxidative stress within the tissues via increasing the reactive oxygen radicals (ROS) through mitochondrial electron transfer chain. 19 ROS are highly toxic to cells, the pathogenesis of this system has been shown to increase lipid peroxidation and nuclear factor kappa b along with transforming growth factor b that causes tissue fibrosis Notes: *p50.05.…”