Anchalee Pongchaidecha

Effects of high-fat diet on insulin receptor function in rat hippocampus and the level of neuronal corticosterone.

AIM Chronic consumption of a high-fat (HF) diet contributes to peripheral insulin resistance and elevated plasma corticosterone. However, the effect of HF consumption on the neurofunctional insulin receptors and neuronal corticosterone level is unclear. We tested the hypothesis that HF consumption can lead to peripheral insulin resistance, elevated neuronal corticosterone, and impaired neuronal responses to insulin. MAIN METHODS Male Wistar rats were fed with normal diet or HF diet for 4, 8 or 12weeks. At the end of each dietary period, plasma was collected for investigating peripheral insulin resistance parameters and corticosterone. Brains were then rapidly removed for studying the function of neuronal insulin receptors (IRs) by extracellular recording in CA1 hippocampus, neuronal IR signaling by immunoblot technique and neuronal corticosterone. KEY FINDINGS Elevated plasma corticosterone level was initially seen in 4-week HF-fed rats. Peripheral insulin resistance developed at 8-week HF-fed rats. However, the elevated neuronal corticosterone level was found at 12-week HF consumption. The neuronal IR response demonstrated by insulin-mediated long-term depression in CA1 hippocampus was diminished in 12-week HF-fed rats. The phosphorylation levels of neuronal IR, IR substrate 1 and Akt/PKB were decreased in 12-week HF-fed rats with no change in these proteins. There was a correlation among peripheral insulin resistance, neuronal stress (elevated neuronal corticosterone), and neuronal insulin resistance in HF group. SIGNIFICANCE Our findings suggest that HF consumption can lead to the elevation of corticosterone and peripheral insulin resistance, which could contribute to neuronal insulin resistance and neuronal stress.

Effects of curcuminoid supplement on cardiac autonomic status in high-fat-induced obese rats.

OBJECTIVE Sudden cardiac death in obesity is frequently associated with sympathetic activation due to an elevated plasma free-fatty acid (FFA) level. Curcuminoids, the phenolic yellowish pigments of turmeric, display antioxidative and lipid-lowering activities. We hypothesized that curcuminoids ameliorate cardiac sympathovagal disturbance in high-fat-induced obese rats. METHODS Male Wistar rats were divided into five groups. A normal-diet control (NDC) group received a normal-fat diet (12% calories as fat) and a high-fat-diet control (HDC) group received a high-fat diet (60% calories as fat) for 12 wk. Three other groups received high-fat diets with curcuminoid supplement at concentrations of 30mg (HD(30)), 60mg (HD(60)), and 90mg (HD(90)) per kilogram of body weight every day for 12 wk. Heart rate variability was determined to assess cardiac autonomic status at weeks 0 and 12. RESULTS Body weight, visceral fat mass, plasma FFA, and glucose levels increased significantly in the HDC group compared with the NDC group. Low frequency power in normalized units (LFnu) and the ratio of LF to high-frequency power (HF) in the HDC group were significantly higher, whereas HFnu in the HDC group was significantly lower than in the NDC group. Plasma FFA levels correlated significantly with LFnu and LF/HF ratio. Compared with the HDC group, plasma FFA, glucose levels, LFnu, and LF/HF ratio were significantly decreased in the HF(30), HF(60), and HF(90) groups. CONCLUSION Elevated plasma FFA in high-fat-induced obese rats is associated with an increased LF/HF ratio, an expression of sympathovagal disturbance. Curcuminoid supplementation ameliorates cardiac autonomic imbalance in high-fat-fed rats, probably due to its lipid-lowering effect.

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.

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.

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.

Antioxidant and Renoprotective Effects of Spirogyra neglecta (Hassall) Kützing Extract in Experimental Type 2 Diabetic Rats

Spirogyra neglecta extract (SNE) has shown antihyperglycemia and antihyperlipidemia in type 2 diabetic mellitus (T2DM) rats. This study investigated the antioxidant and renoprotective effects of SNE in T2DM rats induced by high-fat diet with low-single dose streptozotocin. T2DM rats were fed daily with SNE (0.25, 0.5, and 1 g/kg BW) for 12 weeks. Renal morphology, malondialdehyde levels, qPCR, and western blotting were analyzed. Renal cortical slices were used to determine renal transport of organic anions, which are estrone sulfate and para-aminohippurate, mediated through organic anion transporter 3-Oat3. Insulin and PKCζ were known to activate Oat3 function while it was inhibited by PKCα. Compared to T2DM, plasma glucose, triglyceride, insulin resistance, renal morphology, and malondialdehyde levels were significantly improved by SNE supplementation. Reduced glutathione peroxidase and nuclear factor κB expressions were related to antioxidant effect of SNE. Oat3 mRNA and protein were not different among groups, but insulin-stimulated rOat3 followed by anion uptakes was abolished in T2DM. This was restored in the slices from SNE treatment. The mechanism of SNE-improved Oat3 was associated with PKCα and PKCζ expressions and activities. These findings indicate that SNE has beneficial effects on renal transport through antioxidant enzymes and PKCs in T2DM rats.

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 (TGFβ1), 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 TGFβ1 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 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 pinocembrins antiapoptotic and anti-oxidative stress effects and its ability to increase the phosphorylation of Cx43 in ischemic myocardium.

The roles of sodium-glucose cotransporter 2 inhibitors in preventing kidney injury in diabetes

Diabetic nephropathy (DN) is the leading cause of end stage renal disease (ESRD) worldwide. The early effective treatment of high plasma glucose could delay or prevent the onset of DN. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new target treatments for ameliorating high plasma glucose and help to maintain glucose homeostasis in diabetic patients. Reduced renal glucose reabsorption by SGLT2 inhibition seems to have high potential to improve glycemic control in diabetes mellitus (DM) not only through glucose lowering but also through glucose-independent effects such as blood pressure-lowering and direct renal effects in diabetes. Of note, the important events in the pathogenesis of glucose-induced renal injury and DN including oxidative stress, inflammation, fibrosis and apoptosis conditions have shown to be ameliorate after the treatment with SGLT2 inhibitors. Interestingly, SGLT2 inhibitors have been reported to reduce albuminuria in DM via an activation of renal tubuloglomerular feedback by increased macula densa sodium and chloride delivery, leading to afferent vasoconstriction and attenuated diabetes-induced renal hyperfiltration. These effects also help to conserve glomerular integrity. Thus, the treatment of diabetes mellitus using SGLT2 inhibitors could be one of the effective approach for the management of diabetic-associated kidney disease like DN. This review summarizes the up to date information and discusses the bidirectional relationship between the SGLT2 inhibitor treatments and the renal functions that are available from both basic research and clinical reports. The details of renal outcomes of SGLT2 inhibitors in DN are also provide in this review.

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

ABSTRACT 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) (30 mg/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 PKC&agr;, 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. Graphical abstract Figure. No caption available. HighlightsDiacerein is able to ameliorate insulin resistance in obese rats.Diacerein can attenuate oxidative stress in kidney of obese rats.Diacerein can decrease proinflammatory cytokine in kidney of obese rats.Impaired renal function is restored by diacerein treatment.