Long-term treatment with a beta-blocker timolol attenuates renal-damage in diabetic rats via enhancing kidney antioxidant-defense system

Abstract

The factors with increasing diabetes-prevalence lead to significant global increases in chronic kidney disease. Since hyperglycemia generates more ROS and attenuates cellular antioxidant-defense mechanisms, numerous studies demonstrated that hyperglycemia-induced oxidative stress played a major role in the extracellular matrix expansion in tissues. Although no direct relation between activation of beta-adrenergic (β-AR) system and kidney disease in diabetes and since β-blockers demonstrate marked beneficial effects due to their scavenging free radicals and/or acting as an antioxidant in diabetic animal studies, the eventual objective of the present study was to determine whether timolol-treatment of streptozotocin-induced diabetic rats (5 mg/kg, daily following diabetes-induction, for 12-week) has advantage to prevent hyperglycemia-induced renal-damage via enhancing the depressed antioxidant defense in the kidney. Light microscopy data and their quantification demonstrated that timolol-treatment prevented basically glomerular hypertrophy, expansion in mesangium cell size, thickening and fibrosis in glomerular basement membrane, and accumulation of glycogen into tubular epithelial cells. Additionally, electron microscopy data demonstrated that timolol-treatment could also prevent diabetes-induced changes in the kidney tissue such as hypertrophy in podocytes, lost of filtration gaps and slit-diaphragms, and vacuolization in the distal tubular cells. Biochemical analysis basically on enzymes of antioxidant-defense system, including glutathione-S-transferase, glutathione reductase, and glucose-6-phosphate dehydrogenase, further supported that diabetes-induced damage in the kidney is mostly dependent on the increased oxidative stress and timolol, having an antioxidant-like action, could protect the kidney against hyperglycemia-induced damage without normalization of high-blood glucose level. Consequently, it can be suggested that although β-blockers are widely used for the treatment of cardiovascular diseases, β-blocker therapy of diabetics seems to be a new therapeutic approach against hyperglycemia-induced kidney damage in diabetic patients.

Effects of timolol treatment on pancreatic antioxidant enzymes in streptozotocin-induced diabetic rats: An experimental and computational study

“…Streptozotocin is an antibiotic that is toxic to pancreatic islet β-cells and is commonly used to produce DM, and streptozotocin injection has been shown to produce oxidative stress, lipid peroxidation, and biochemical alterations such as reduced glutathione level and reduced glutathione and oxidised glutathione ratio and glutathione redox cycle enzymes (22, 32, 33, 34, 35). Therefore, researchers trying to find various extracts, drug-like molecules, antioxidant supplementations, vitamins, drug molecules to increase the enzyme activities which are responsible for improving GSH redox state, increasing reduced glutathione pool, and increase GSH/GSSG ratio and for cellular prevention against glucose toxicity, oxidative stress, enzyme activity normalizations in diabetic animal models (22, 35, 36, 37, 38, 39). In the present study, we have demonstrated that timolol treatment of STZ-induced diabetic rats had no noteworthy effect on high blood glucose level, while this treatment induced marked protection against hyperglycemia induced depressed activities of G6PD and 6PGDH in pancreatic tissue from STZ-induced diabetic rats.…”

“…The experimental diabetic animal procedures, including timolol-treatment, were performed as described previously. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg body weight and dissolved in 0.1 mol/L citrate buffer, pH 4.5) in 3-month-old adult male Wistar rats (200–250 g body wt) (22). Rats with a blood glucose level >3 fold of controls were kept as diabetics (DM group) and tail vein fasting blood glucose levels were measured using a glucose analyser (Glucotrend, Roche).…”

“…ACs catalyse the synthesis of the signalling molecule cAMP, which is an important second messenger and plays a prominent role in insulin secretion from β-cells of pancreatic islets and is implicated as a therapeutic target for diabetes (18, 19, 20) as well. In our previous studies, we showed that a nonspecific β-AR blocker timolol treatment of diabetic rats presented a marked protective action in cardiovascular system disorders and kidney damage, in part, due to the prevention of endoplasmic reticulum stress, similar to the action of known antioxidants (21, 22).…”

“…Even in early studies, timolol was used in treatment after myocardial infarction in diabetic patients, migraine and disorders such as tremor. Its chemical structure is given in Figure 1 (20, 21, 22, 23, 24, 25). Taken into consideration its multifunctional actions, herein we aimed to investigate first the effects of timolol treatment on pentose phosphate pathway enzyme activities together with the cAMP level in STZ-induced diabetic rat pancreas tissue.…”

High-carbohydrate diet-induced myocardial remodelling in rats

“…Light microscopic evaluation was performed as described previously (24). Briefly, the excised heart samples were fixed in phosphate buffer/10% formaldehyde and dehydrated through a series of alcohol solutions.…”