thioacetamide and Kidney-Diseases

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine with chemokine properties released by various immune and non-immune cells. It contributes to the pathogenesis of many inflammatory, autoimmune diseases and malignant tumors.. Our study aimed to investigate the role of betaine in the modulation of MIF-mediated oxidative stress, inflammation, and fibrogenesis during toxic kidney damage induced by thioacetamide (TAA).. The experiment is performed on wild-type and knockout MIF-/- C57BL/6 mice. They are randomly divided into groups: Control; Bet-group, received betaine (2% wt/v dissolved in drinking water); MIF-/- mice group; MIF-/- + Bet; TAA-group, treated with TAA (200 mg/kg b.w.), intraperitoneally, 3x/week/8 weeks); TAA+Bet; MIF-/-+TAA, and MIF-/- + TAA+Bet group. After eight weeks of treatment, animals are sacrificed and kidney samples are taken to determine oxidative stress parameters, proinflammatory cytokines, profibrogenic factors, and histopathology of renal tissue.. In MIF-/-mice, TAA decreases malondialdehyde (MDA) concentration, IL-6, tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB) and increases superoxide dismutases (SOD) and catalase (CAT) activities, as well as glutathione (GSH) content in kidneys, compared to TAA group. Betaine alleviates the mechanism of MIF-mediated effects in TAA-induced nephrotoxicity, reducing MDA, IL-6, TNF-α, TGF-β1, and PDGF-BB, and increasing SOD and CAT activity, as well as GSH levels.. MIF mediates TAA-induced nephrotoxicity by increasing oxidative stress, inflammation, and profibrogenic mediators. MIF-targeted therapy could potentially alleviate oxidative stress and inflammation in the kidney, as well as pathohistological changes in renal tissue, but the exact mechanism of its action is not completely clear. Betaine alleviates MIF nephrotoxic effects by increasing the antioxidative capacity of kidney cells, and decreasing lipid peroxidation and cytokine production in the renal tissue. It suggests that betaine can be used for the prevention of kidney damage.

Topics: Animals; Antioxidants; Becaplermin; Betaine; Glutathione; Inflammation; Interleukin-6; Kidney Diseases; Liver; Macrophage Migration-Inhibitory Factors; Mice; Mice, Inbred C57BL; Oxidative Stress; Superoxide Dismutase; Thioacetamide; Transforming Growth Factor beta1; Tumor Necrosis Factor-alpha

Cilostazol and verapamil are widely used cardiovascular drugs, explored a beneficial effect on different organs-induced toxicities. We investigated whether the Nrf2 (nuclear erythroid factor 2) and its downstream pathway are involved in the protective role of these drugs against TAA-induced renal damage. Renal biomarkers (creatinine and urea) and histopathology were observed. Antioxidant and oxidant indicators; superoxide dismutase (SOD), reduced glutathione (GSH), malondialdehyde (MDA) and total nitrite (NO) were also measured. Antioxidant markers like; Nrf2/hemoxegenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions were determined by ELISA and immunohistochemistry. Cilostazol and verapamil pretreatment improved serum creatinine and urea elevation. Examined drugs also have an ameliorative effect on TAA-induced elevation in MDA and NO activities and antioxidant enzymes; SOD and GSH. Additionally, the pretreated drugs significantly up-regulated Nrf2/HO-1/NQO-1 expression levels. In conclusion, cilostazol and verapamil exerted their protective effects partially via a Nrf2/HO-1/NQO-1 activation pathway with anti-oxidant roles.

Topics: Animals; Antioxidants; Cilostazol; Cytoprotection; Disease Models, Animal; Heme Oxygenase (Decyclizing); Kidney; Kidney Diseases; Male; NAD(P)H Dehydrogenase (Quinone); NF-E2-Related Factor 2; Oxidative Stress; Rats; Signal Transduction; Thioacetamide; Verapamil

Oxidative stress due to abnormal induction of reactive oxygen species (ROS) molecules is believed to be involved in the etiology of many diseases. Evidences suggest that ROS is involved in nephrotoxicity through frequent exposure to industrial toxic agents such as thioacetamide (TAA). The current investigation was designed to explore the possible protective effects of the leaves of Vitex negundo(VN) extract against TAA-induced nephrotoxicity in rats.. Twenty four Sprague Dawleyrats were divided into four groups: (A) Normal control, (B) TAA (0.03% w/v in drinking water), (C) VN100 (VN 100 mg/kg + TAA) and (D) VN300 (VN 300 mg/kg + TAA). Blood urea and serum creatinine levels were measured,supraoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) levels of renal tissue were assayed. Histopathological analysis together with the oxidative stress nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox in kidney sections were examined in all experimental groups.. Blood urea and serum creatinine levels were increased in TAA group as a result of the nephrotoxicity compared to the VN100 and VN300 groups where, the levels were significantly decreased (p < 0.05). Renal MDA level was significantly decreased (p < 0.05) in the VN-treated groups with increased CAT and SOD activities compared to the TAA group. Light microscopic examination of renal tissues stained by H&E stain and Masson's Trichrome for TAA-treated groups revealed severe histopathological changes, whereas specimens obtained from VN-treated groups showed only mild changes. These findings were supported by immunohistochemical results.. VN extract acts as a natural potent antioxidant to prevent ongoing TAA-induced nephrotoxicity in rats, both biochemically and morphologically.

Topics: Administration, Oral; Animals; Antioxidants; Catalase; Humans; Kidney; Kidney Diseases; Male; Malondialdehyde; Oxidative Stress; Plant Extracts; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Superoxide Dismutase; Thioacetamide; Vitex

We studied whether administration of nitroflurbiprofen (HCT-1026), a cyclooxygenase inhibitor with nitric oxide (NO)-donating properties, modulates the increased intrahepatic vascular tone in portal hypertensive cirrhotic rats.. In vivo hemodynamic measurements (n = 8/condition) and evaluation of the increased intrahepatic resistance by in situ perfusion (n = 5/condition) were performed in rats with thioacetamide-induced cirrhosis that received either nitroflurbiprofen (45 mg/kg), flurbiprofen (30 mg/kg, equimolar concentration to nitroflurbiprofen), or vehicle by intraperitoneal injection 24 hours and 1 hour prior to the measurements. Additionally, we evaluated the effect of acute administration of both drugs (250 micromol/L) on the intrahepatic vascular tone in the in situ perfused cirrhotic rat liver (endothelial dysfunction and hyperresponsiveness to methoxamine) and on hepatic stellate cell contraction in vitro. Typical systemic adverse effects of nonsteroidal anti-inflammatory drugs, such as gastrointestinal ulceration, renal insufficiency, and hepatotoxicity, were actively explored.. In vivo, nitroflurbiprofen and flurbiprofen equally decreased portal pressure (8 +/- 0.8 and 8.4 +/- 0.1 mm Hg, respectively, vs 11.8 +/- 0.6 mm Hg) and reduced the total intrahepatic vascular resistance. Systemic hypotension was not aggravated in the different treatment groups (P = .291). In the perfused cirrhotic liver, both drugs improved endothelial dysfunction and hyperresponsiveness. This was associated with a decreased hepatic thromboxane A(2)-production and an increased intrahepatic nitrate/nitrite level. In vitro, nitroflurbiprofen, more than flurbiprofen, decreased hepatic stellate cells contraction. Flurbiprofen-treated rats showed severe gastrointestinal ulcerations (bleeding in 3/8 rats) and nefrotoxicity, which was not observed in nitroflurbiprofen-treated cirrhotic rats.. Treatment with nitroflurbiprofen, an NO-releasing cyclooxygenase inhibitor, improves portal hypertension without major adverse effects in thioacetamide-induced cirrhotic rats by attenuating intrahepatic vascular resistance, endothelial dysfunction, and hepatic hyperreactivity to vasoconstrictors.

Topics: Animals; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelium, Vascular; Flurbiprofen; Hypertension, Portal; Kidney Diseases; Liver; Liver Circulation; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitric Oxide Donors; Peptic Ulcer; Perfusion; Portal Pressure; Rats; Rats, Wistar; Thioacetamide; Thromboxane A2; Vascular Resistance; Vasoconstriction; Vasodilation

Experimental liver injury with different stages was provoked in rats with daily injected doses of thioacetamide (ThAA). The dose recommended for both male and female rats was 50 mg/kg body weight. The liver damages caused were acute, subacute, cirrhotic and necrotic, with a traumatization period of 2, 7, 14 and 21 days. The loss of body weight under traumatization, indicating osteopenia, was in the case of female rats during the first experimental week markedly accelerated, and in the two subsequent weeks apparently inhibited when compared to male rats. The loss of body weight of male rats revealed a progressive fall. Vital staining was made giving intraperitoneally 200 mg/kg body weight of alizarin red S (ARS). The staining intensity was improved in the acute stage for both calvaria and tibia and in the necrotic stage for tibia only. It was impaired in the subacute stage for calvaria and tibia and in the necrotic stage for calvaria only. Prolonged traumatization with ThAA causes pathological defects in the liver and kidneys. Furthermore, the epiphyseal cartilage of necrotic-stage rats was bright red without any ARS staining.

Topics: Animals; Anthraquinones; Body Weight; Bone and Bones; Bone Resorption; Calcium; Cartilage; Chemical and Drug Induced Liver Injury; Coloring Agents; Female; Kidney Diseases; Liver; Liver Diseases; Male; Rats; Sex Factors; Staining and Labeling; Thioacetamide

Thioacetamide given orally to rats produces centrolobular hepatic necrosis and also causes death of the cells in the terminal portion of the proximal renal tubule. The morphologic changes observed during the course of the renal toxicity include the early and transient appearance of apical dense bodies, which appear to fuse to form large lysosomes, and the appearance of nucleolar hypertrophy, reminiscent of the same change seen in the hepatocytes. In addition a variety of changes described in lethally injured tubular cells in other toxicities appear. A diuresis, which lasts for 5 days, coincides with the appearance of tubular cell destruction. The mechanism of cell injury due to thioacetamide is not identified, but the temporal sequence of morphologic and physiologic change is consistent with both a relative concentration of the thioacetamide in the proximal tubule and its potential conversion to a putative proximate toxin.

Topics: Acetamides; Animals; Cell Nucleolus; Chemical and Drug Induced Liver Injury; Diuresis; Kidney Diseases; Kidney Tubules, Proximal; Lysosomes; Male; Microscopy, Electron; Rats; Thioacetamide