Our study suggests that a high-fat diet induces fatty kidneys, aggravation of blood pressure and renal inflammation in the SHR. Blockade of oxidative stress by tempol or of RAS by candesartan ameliorates the increase in blood pressure and renal inflammation and improves intrarenal lipid accumulation. Therefore, antioxidants or angiotensin receptor blockers can prevent diet-induced hypertension and renal inflammation in hypertensive rats.

We investigated the effects of a high-fat (HF) diet and peroxisome proliferator-activated receptor (PPAR)-a activation on the intrarenal lipotoxicity associated with the renin-angiotensin system (RAS) and oxidative stress using spontaneously hypertensive (SHR) rats. Male SHR and Wistar-Kyoto (WKY) rats at 8 weeks of age were fed either a normal-fat diet or an HF diet without or with fenofibrate treatment for 12 weeks. Severe intrarenal lipid accumulation was noted in the SHR rats fed an HF diet than in WYK rats fed an HF diet (Po0.05). This lipid accumulation was associated with a 70% decrease in renal PPARa expression in SHR rats, whereas an HF diet increased the expression of PPARa in WKY rats by threefold. An HF diet also activated intrarenal, not systemic, RAS and induced oxidative stress associated with reduced nitric oxide (NO) bioavailability. By contrast, fenofibrate attenuated weight gain, fat mass and insulin resistance. Fenofibrate recovered HF diet-induced decreases in intrarenal PPARa expression and fat accumulation, and abolished intrarenal RAS activation and oxidative stress in SHR-HF animals (Po0.01). These activities conferred protection against increased blood pressure (BP), glomerulosclerosis and renal inflammation. Keywords: obesity; oxidative stress; PPARa; renal inflammation; renin-angiotensin system INTRODUCTION Currently, the prevalence of hypertension and chronic renal disease continues to increase among obese individuals. 1,2 It has been suggested that the development and progression of hypertension in an obese patient induces the activation of the systemic renin-angiotensin system (RAS) and the sympathetic nervous system. 3,4 In addition, it increases asymmetric dimethylarginine concentrations and vascular tone created by the reduced bioavailability of nitric oxide (NO) owing to increased oxidative stress. 5,6 Recent reports have demonstrated that it is not the systemic but the local (tissue specific) RAS activation that causes hypertension and renal damage 7-9 associated with local oxidative stress. [10][11][12] It has been shown that oxidative stress in kidneys of diabetic animals, measured by the electron spin resonance imaging technique, 10 high-performance liquid chromatography 13 and immunohistochemistry, 14 can be ameliorated by RAS inhibition.

Bcl-2 interacting cell death suppressor (Bis), also known as Bag3 or CAIR-1, is involved in antistress and antiapoptotic pathways. In addition to Bcl-2, Bis binds to several proteins, suggesting it has diverse functions in normal and pathological conditions. To better define the physiological function of Bis in vivo, we developed bis-deficient mice with a cre-loxP system. Targeted disruption of exon 4 of the bis gene was demonstrated by Southern blotting and PCR, and Western blotting showed that no intact or truncated Bis protein was synthesized in bis(-/-) mice. While heterozygotes were fertile and appeared normal, Bis-deficient mice showed growth retardation and died by 3 wk after birth. The relative weight of the thymus and spleen was reduced and the total numbers of white blood cells, splenocytes, and thymocytes were significantly reduced compared with wild-type littermates. Serum profiles indicated significant hypoglycemia as well as decrease in triglyceride and cholesterol levels. Expression profiles of metabolic genes indicated that gluconeogenesis and beta-oxidation are activated in the liver of bis(-/-) mice. This activation, as well as a decrease in peripheral fat and an induction of fatty liver, appears to be an adaptive response to hypoglycemia. Our study reveals that the absence of Bis has considerable influences on postnatal growth and survival, possibly due to a nutritional impairment.

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Glioblastoma stem cells (GSCs) are a subpopulation of highly tumorigenic and stem-like cells that are responsible for resistance to conventional therapy. Bcl-2-intreacting cell death suppressor (BIS; also known as BAG3) is an anti-apoptotic protein that is highly expressed in human cancers with various origins, including glioblastoma. In the present study, to investigate the role of BIS in GSC subpopulation, we examined the expression profile of BIS in A172 and U87-MG glioblastoma cell lines under specific in vitro culture conditions that enrich GSC-like cells in spheres. Both BIS mRNA and protein levels significantly increased under the sphere-forming condition as compared with standard culture conditions. BIS depletion resulted in notable decreases in sphere-forming activity and was accompanied with decreases in SOX-2 expression. The expression of STAT3, a master regulator of stemness, also decreased following BIS depletion concomitant with decreases in the nuclear levels of active phosphorylated STAT3, while ectopic STAT3 overexpression resulted in recovery of sphere-forming activity in BIS-knockdown glioblastoma cells. Additionally, immunoprecipitation and confocal microscopy revealed that BIS physically interacts with STAT3. Furthermore, BIS depletion increased STAT3 ubiquitination, suggesting that BIS is necessary for STAT3 stabilization in GSC-like cells. BIS depletion also affected epithelial-to-mesenchymal transition-related genes as evidenced by decrease in SNAIL and MMP-2 expression and increase in E-cadherin expression in GSC-like cells. Our findings suggest that high levels of BIS expression might confer stem-cell-like properties on cancer cells through STAT3 stabilization, indicating that BIS is a potential target in cancer therapy.

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The Bis protein is known to be involved in a variety of cellular processes including apoptosis, migration, autophagy as well as protein quality control. Bis expression is induced in response to a number of types of stress, such as heat shock or a proteasome inhibitor via the activation of heat shock factor (HSF)1. We report herein that Bis expression is increased at the transcriptional level in HK-2 kidney tubular cells and A172 glioma cells by exposure to oxidative stress such as H2O2 treatment and oxygen-glucose deprivation, respectively. The pretreatment of HK-2 cells with N-acetyl cysteine, suppressed Bis induction. Furthermore, HSF1 silencing attenuated Bis expression that was induced by H2O2, accompaniedby increase in reactive oxygen species (ROS) accumulation. Using a series of deletion constructs of the bis gene promoter, two putative heat shock elements located in the proximal region of the bis gene promoter were found to be essential for the constitutive expression is as well as the inducible expression of Bis. Taken together, our results indicate that oxidative stress induces Bis expression at the transcriptional levels via activation of HSF1, which might confer an expansion of antioxidant capacity against pro-oxidant milieu. However, the possible role of the other cis-element in the induction of Bis remains to be determined.

Bis (Bag3) is known to be involved in cell survival, migration, the regulating of chaperones, and protein quality control. We reported recently on the production of bis gene-deleted mice, which show early lethality within 3 wk after birth with a phenotype showing severe malnutrition and shrinkage of the thymus. In this report, we provide evidence to show that an intrinsic problem of adrenal gland is the the primary cause for the severe atrophy of the thymus in bis−/− mice. The bis−/− mice show significantly higher levels of corticosterone, but CRH and ACTH levels were considerably lower than those of wild littermates. The transcription of steroidogenic enzymes was increased in the adrenal glands of bis−/− mice, accompanied by an increase in the thickness of the zona reticularis. An analysis of thymus tissue from bis−/− mice revealed that the severe atrophy of the thymus is due to the specific loss of immature double-positive (CD4+CD8+) cortical thymocytes by apoptosis, as evidenced by immunohistochemical examination and flow cytometric analysis, which were restored by injection of an inhibitor of glucocorticoid synthesis. In vitro cultures of thymocytes with increasing doses of dexamethasone exhibited a similar degree of apoptosis between wild and bis−/− thymocytes. The corticosterone levels from fasted wild littermates were one-half those of bis−/− mice, although serum glucose levels were similar. Thus, the deletion of the bis gene resulted in the intrinsic defect in the adrenal gland, leading to a marked increase in glucocorticoid levels, probably upon starvation stress, which accounts for the massive apoptosis of the thymus.