Curcumin protects rats against gentamicin-induced nephrotoxicity by amelioration of oxidative stress, endoplasmic reticulum stress and apoptosis.

CONTEXT: Gentamicin (GM) is an aminoglycoside antibiotic which is commonly used against Gram-negative bacterial infection; however, serious complications including nephrotoxicity could limit its clinical use. OBJECTIVE: The present study examined the protective effects of curcumin (CUR) on endoplasmic reticulum (ER) stress-mediated apoptosis through its antioxidative property in GM-induced nephrotoxicity in rats. MATERIALS AND METHODS: Male Sprague-Dawley rats (n = 3) were divided into six groups to receive normal saline (control), GM (100 mg/kg/day), co-treatment with GM and CUR (100, 200 and 300 mg/kg/day) and CUR (200 mg/kg/day) alone for 15 days by gavage feeding. Then, the renal function, kidney injury as well as oxidative stress, antioxidative markers and ER stress-mediated apoptosis were evaluated. RESULTS: Pre-treatment of CUR rescued the nephrotoxicity in GM-treated rats. Several nephrotoxicity hallmarks were reversed in the CUR-pre-treatment group. At the dose of 200 mg/kg/day, it could significantly lower serum creatinine (from 0.95 to 0.50 mg/dL), blood urea nitrogen (from 35.00 to 23.50 mg/dL) and augmented creatinine clearance (from 0.83 to 1.71 mL/min). The normalized expression of oxidative stress marker, malondialdehyde was decreased (from 13.00 to 5.98) in line with the increase of antioxidant molecules including superoxide dismutase (from 5.59 to 14.24) and glutathione (from 5.22 to 12.53). Furthermore, the renal ER stress and apoptotic protein biomarkers were lowered in CUR treatment. DISCUSSION AND CONCLUSIONS: Our findings pave the way for the application of CUR as a supplement in the prevention of nephrotoxicity and other kidney diseases in the future.

Anthocyanin-rich fraction from black rice, Oryza sativa L. var. indica "Luem Pua," bran extract attenuates kidney injury induced by high-fat diet involving oxidative stress and apoptosis in obese rats.

Obesity is acknowledged as being a world health problem and increases the risk of several chronic diseases including chronic kidney disease. High-fat diet consumption and obesity-related renal disease show a close correlation with increased oxidative stress. Black rice bran extract, (BRE) Oryza sativa L. variety "Luem Pua" contains a high anthocyanin content. This study evaluated the effects of an anthocyanin-rich fraction from BRE on renal function and oxidative stress in obese rats. Male Wistar rats were fed a normal diet (ND) or high-fat diet (HF) for 16 weeks. After this, the rats were given either vehicle (HF), BRE 100 (HF100) or BRE 200 mg/kg/day (HF200) orally for 8 weeks. The HF rats had increased body weight, visceral fat weight, plasma glucose, cholesterol and triglycerides. These parameters were normalized following HF100 administration and showed a decreasing trend with HF200. Serum creatinine and renal cortical MDA were increased in the HF group but these effects were attenuated by BRE. Negative kidney injury and histopathology changes were observed following a HF, but treatment with BRE reversed these deleterious effects. These results suggest that BRE could be used as a food supplement to improve metabolic disturbance and prevent kidney dysfunction in cases of obesity.

Diacerein alleviates kidney injury through attenuating inflammation and oxidative stress in obese insulin-resistant rats.

A link between inflammation with obesity and metabolic syndrome has been found in patients with chronic kidney disease (CKD). Diacerein is an anthraquinone used to treat osteoarthritis that exerts anti-inflammatory action by inhibiting the synthesis and activity of proinflammatory cytokines. This study aimed to investigate the protective effect of diacerein on renal function and renal organic anion transporter 3 (Oat3) function in obese insulin-resistant condition. Obese insulin-resistant rats were induced by feeding a high-fat diet in male Wistar rats for 16 weeks. Diacerein or metformin (positive control) (30mg/kg/day) was administered orally for 4 weeks after insulin resistance had been confirmed. Obese insulin-resistant rats showed an impaired renal function as indicated by the increased serum creatinine and microalbuminuria along with the decreased renal Oat3 function and expression. Importantly, diacerein treatment not only improved insulin resistance but also restored renal function. The decreased renal malondialdehyde level, expressions of PKCα, angiotensin 1 receptor (AT1R), Nrf2, and HO-1, and increased expression of SOD2 were observed in diacerein treatment group, indicating the attenuation of renal oxidative stress condition. Moreover, renal inflammation and renal damage were also alleviated in diacerein-treated rats. Our results demonstrated for the first time that diacerein was effective to improve renal function and renal Oat3 function in obese insulin-resistance condition mediated by suppressing renal oxidative stress and inflammation. These findings suggest that anti-inflammatory agents can be used therapeutically to improve metabolic disorder and prevent organ dysfunctions in pre-diabetic condition.

Anthocyanin-rich Riceberry bran extract attenuates gentamicin-induced hepatotoxicity by reducing oxidative stress, inflammation and apoptosis in rats.

Liver plays an important role in the detoxification and metabolic elimination of various drugs and harmful substances. The damaging effects on the liver tissue treated with gentamicin are multi-factorial and their mechanisms remain unclear. This study aimed to investigate the possible protective effects of anthocyanin-rich Riceberry bran extract on gentamicin-induced hepatotoxicity in rats. Riceberry bran extract was given by oral administration 30min before gentamicin injection for 15 consecutive days. Serum levels of liver marker enzymes, AST and ALT, were significantly elevated and the total serum protein level was markedly reduced in gentamicin-treated rats. Gentamicin injection led to the significant increase in hepatic MDA level and decrease SOD expression. Liver inflammation and apoptosis were observed in gentamicin-treated rats as indicated by the increases in NF-κB, TNF-αR1, COX2, and iNOS, caspase-3, Bax, and decrease in Bcl-XL expressions. Riceberry bran extract significantly prevented gentamicin-induced the elevations of serum AST, ALT and the reduction of serum total protein. These were related to the inhibition of oxidative stress, inflammation and apoptosis in Riceberry bran extract treatment. These findings suggest that anthocyanin-rich Riceberry bran extract can prevent liver dysfunction and damage induced by gentamicin, possibly through its antioxidant, anti-inflammatory and anti-apoptotic effects.

Riceberry bran extract prevents renal dysfunction and impaired renal organic anion transporter 3 (Oat3) function by modulating the PKC/Nrf2 pathway in gentamicin-induced nephrotoxicity in rats.

PURPOSE: This study investigated the protective effects of Riceberry bran extract (RBBE) on renal function, and the function and expression of renal organic anion transporter 3 (Oat3) in gentamicin-induced nephrotoxicity in rats and explored the mechanisms for its protective effects. MATERIAL AND METHODS: Male Sprague Dawley rats (n= 42) were divided into six groups to receive normal saline, gentamicin (100mg/kg), co-treatment of gentamicin and RBBE (at dose of 250, 500 and 1000mg/kg), and RBBE (at dose of 1000mg/kg) only, for consecutive fifteen days. Renal function, oxidative and antioxidative markers, the function and expression of Oat3 and histological changes in the kidney were evaluated. RESULTS: Elevation of BUN, serum creatinine levels and reduction in urine creatinine and creatinine clearance indicated decreased renal function in the gentamicin-treated rats. The decrease of [3H]ES uptake in the renal cortical slices of these rats, reflecting the attenuation of Oat3 transport function that was accompanied by decreased expression of Oat3. Moreover, increased MDA level and reduced superoxide dismutase (SOD) and glutathione (GSH) activities were found in gentamicin-treated rats compared to the control group. These changes were associated with the upregulated PKCα, Nrf-2, Keap 1, NQO-1 and HO-1 expressions in kidneys. RBBE treatment improved the renal function and Oat3 transport function and expression in gentamicin-treated rats. The oxidative status was also restored by RBBE treatment. CONCLUSION: RBBE protects kidney injury by its antioxidant effect, subsequently leading to modulation of the PKC/Nrf2 antioxidant defense pathway.

Amelioration of Renal Inflammation, Endoplasmic Reticulum Stress and Apoptosis Underlies the Protective Effect of Low Dosage of Atorvastatin in Gentamicin-Induced Nephrotoxicity.

Gentamicin is a commonly used aminoglycoside antibiotic. However, its therapeutic use is limited by its nephrotoxicity. The mechanisms of gentamicin-induced nephrotoxicity are principally from renal inflammation and oxidative stress. Since atorvastatin, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exerts lipid-lowering effects, antioxidant, anti-inflammatory as well as anti-apoptotic effects, this study aimed to investigate the protective effects of atorvastatin against gentamicin-induced nephrotoxicity. Male Sprague Dawley rats were used and nephrotoxicity was induced by intraperitoneal injection of gentamicin, 100 mg/kg/day, for 15 days. Atorvastatin, 10 mg/kg/day, was administered by orally gavage 30 min before gentamicin injection on day 1 to 15 (pretreatment) or on day 10 to15 (delayed treatment). For only atorvastatin treatment group, it was given on day 1 to 15. At the end of the experiment, kidney weight, blood urea nitrogen and serum creatinine as well as renal inflammation (NF-κB, TNFαR1, IL-6 and iNOS), renal fibrosis (TGFß1), ER stress (calpain, GRP78, CHOP, and caspase 12) and apoptotic markers (cleaved caspase-3, Bax, and Bcl-2) as well as TUNEL assay were determined. Gentamicin-induced nephrotoxicity was confirmed by marked elevations in serum urea and creatinine, kidney hypertrophy, renal inflammation, fibrosis, ER stress and apoptosis and attenuation of creatinine clearance. Atorvastatin pre and delayed treatment significantly improved renal function and decreased renal NF-κB, TNFαR1, IL-6, iNOS and TGFß1 expressions. They also attenuated calpain, GRP78, CHOP, caspase 12, Bax, and increased Bcl-2 expressions in gentamicin-treated rat. These results indicate that atorvastatin treatment could attenuate gentamicin-induced nephrotoxicity in rats, substantiated by the reduction of inflammation, ER stress and apoptosis. The effect of atorvastatin in protecting from renal damage induced by gentamicin seems to be more effective when it beginning given along with gentamicin or pretreatment.

Pinocembrin attenuates gentamicin-induced nephrotoxicity in rats.

Oxidative stress mediated apoptosis of renal tubular cells is a major pathology of gentamicin-induced nephrotoxicity, which is one of the prevailing causes of acute renal failure. Pinocembrin is a major flavonoid found in rhizomes of fingerroot (Boesenbergia pandurata). It has pharmacological and biological activities including antimicrobial, anti-inflammatory, and antioxidant effects. Preclinical studies have suggested that pinocembrin protects rat brain and heart against oxidation and apoptosis induced by ischemia-reperfusion. The aim of the current study was to investigate the mechanisms of renoprotection elicited by pinocembrin in gentamicin-induced nephrotoxicity. Nephrotoxicity was induced in rats by intraperitoneal injection (i.p.) of gentamicin, and pinocembrin was administered via i.p. 30 min before gentamicin treatment for 10 days. Gentamicin-induced nephrotoxicity was indicated by the reduced renal function and renal Oat3 function and expression. Gentamicin treatment also stimulated Nrf2, HO-1, and NQO1, as well as the pro-apoptotic proteins Bax and caspase-3, concomitant with the attenuation of Bcl-XL expression in the renal cortical tissues. Pinocembrin pretreatment improved renal function and renal Oat3 function and reduced oxidative stress and apoptotic conditions. These findings indicate that pinocembrin has a protective effect against gentamicin-induced nephrotoxicity, which may be due in part to its antioxidant and anti-apoptotic effects, subsequently leading to improved renal function.

Atorvastatin improves renal organic anion transporter 3 and renal function in gentamicin-induced nephrotoxicity in rats.

What is the central question of this study? This study was designed to determine the renoprotective effects of atorvastatin treatment in an experimental model of gentamicin-induced nephrotoxicity through modulating the Nrf2 pathway by decreasing the oxidative stress. What is the main finding and its importance? Atorvastatin exerts a nephroprotective effect by attenuating oxidative stress, protecting renal function and renal organic anion transporter 3 function from the effects of gentamicin. Atorvastatin might protect the tissues via its antioxidant property and by modulating the antioxidant enzymes through the Nrf2 signalling pathway, which may be the underlying mechanisms of these protective effects. Recent evidence demonstrates that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, exert not only lipid-lowering effects but also antioxidant, anti-inflammatory and anti-apoptotic effects. Nephrotoxicity, a serious side-effect of gentamicin, is related to an increase in reactive oxygen species in the kidney. This study was designed to determine the renoprotective effects of atorvastatin treatment in an experimental model of gentamicin-induced nephrotoxicity. Male Sprague-Dawley rats were used. Nephrotocixity was induced by i.p. injection of gentamicin, 100 mg kg(-1)  day(-1) , for 15 days. Atorvastatin, 10 mg kg(-1)  day(-1) , was administered by gavage 30 min before gentamicin injection (pretreatment) for 15 days or only on days 10-15 (post-treatment). Renal function and renal organic anion transporter 3 (Oat3) function and expression were examined. Gentamicin-treated rats demonstrated impaired renal function by attenuation of creatinine clearance and increased oxidative stress. Gentamicin treatment also decreased renal Oat3 function and expression as shown by decreased [(3) H]estrone sulfate uptake into renal cortical slices and decreased expression. The protein expressions of protein kinase C, Nrf2, NAD(P)H:quinone oxidoreductase 1, haeme oxygenase 1 and glutamate-cysteine ligase were markedly increased in gentamicin-treated rats, indicating the increase in oxidative stress. Administration of atorvastatin improved renal function and alleviated oxidative stress, and atorvastatin pretreatment had a greater ability to decrease oxidative stress than atorvastatin post-treatment. These effects helped to preserve renal function and Oat3 function and expression. These results indicate that atorvastatin has a renoprotective effect against gentamicin-induced nephrotoxicity by decreasing overoxidation in the kidney, and might be used in conjunction with gentamicin to protect against renal damage.

Pinocembrin reduces cardiac arrhythmia and infarct size in rats subjected to acute myocardial ischemia/reperfusion.

Oxidative stress plays an important role in the pathogenesis of ischemia/reperfusion (I/R) injury induced by cardiac dysfunction. Pinocembrin (5,7-dihydroxyflavanone) is a flavonoid found in propolis and in rhizomes of fingerroot (Boesenbergia pandurata) that is reported to have pharmacological properties including antimicrobial, antioxidant, and anti-inflammatory activities. The cardioprotective effects of pinocembrin in an I/R model were investigated in this study. Male Wistar rats (n = 20) were randomly divided into 2 groups to receive either pinocembrin (30 mg/kg body weight) or the vehicle intravenously. Thirty minutes later, the left anterior descending coronary artery of each rat was ligated for 30 min, and then reperfusion was allowed for 120 min. Cardiac function improved in the pinocembrin-treated group: the time to first ventricular fibrillation (VF) was significantly longer in the treated group (550 ± 54 s) than in the vehicle-only control group (330 ± 27 s) (p < 0.05). VF incidence and arrhythmia score were lower and infarcts were 49% smaller in the pinocembrin-treated group than in the control group (p < 0.05). In the pinocembrin-treated group, malondialdehyde levels and Bax/Bcl-2 ratios decreased, and the ratio of phosphorylated connexin 43 (phospho-Cx43) to total Cx43 increased in infarcted tissues compared with the non-infarcted area (p < 0.05). Pinocembrin exhibited cardioprotective effects during I/R, evidenced by improved cardiac function, fewer arrhythmias, and smaller infarcts in treated hearts than in controls. These benefits may be due to pinocembrin's antiapoptotic and anti-oxidative stress effects and its ability to increase the phosphorylation of Cx43 in ischemic myocardium.

Impaired insulin signaling affects renal organic anion transporter 3 (Oat3) function in streptozotocin-induced diabetic rats.

Organic anion transporter 3 (Oat3) is a major renal Oats expressed in the basolateral membrane of renal proximal tubule cells. We have recently reported decreases in renal Oat3 function and expression in diabetic rats and these changes were recovered after insulin treatment for four weeks. However, the mechanisms by which insulin restored these changes have not been elucidated. In this study, we hypothesized that insulin signaling mediators might play a crucial role in the regulation of renal Oat3 function. Experimental diabetic rats were induced by a single intraperitoneal injection of streptozotocin (65 mg/kg). One week after injection, animals showing blood glucose above 250 mg/dL were considered to be diabetic and used for the experiment in which insulin-treated diabetic rats were subcutaneously injected daily with insulin for four weeks. Estrone sulfate (ES) uptake into renal cortical slices was examined to reflect the renal Oat3 function. The results showed that pre-incubation with insulin for 30 min (short term) stimulated [3H]ES uptake into the renal cortical slices of normal control rats. In the untreated diabetic rats, pre-incubation with insulin for 30 min failed to stimulate renal Oat3 activity. The unresponsiveness of renal Oat3 activity to insulin in the untreated diabetic rats suggests the impairment of insulin signaling. Indeed, pre-incubation with phosphoinositide 3-kinase (PI3K) and protein kinase C zeta (PKCζ) inhibitors inhibited insulin-stimulated renal Oat3 activity. In addition, the expressions of PI3K, Akt and PKCζ in the renal cortex of diabetic rats were markedly decreased. Prolonged insulin treatment in diabetic rats restored these alterations toward normal levels. Our data suggest that the decreases in both function and expression of renal Oat3 in diabetes are associated with an impairment of renal insulin-induced Akt/PKB activation through PI3K/PKCζ/Akt/PKB signaling pathway.