PPAR-Alpha Agonist Fenofibrate Induces Renal CYP Enzymes and Reduces Blood Pressure and Glomerular Hypertrophy in Zucker Diabetic Fatty Rats

Zhao, Xueying; Li, Lingyun

doi:10.1159/000116885

Cited by 43 publications

(42 citation statements)

References 79 publications

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“…It has been recently reported that inhibition of cyclin D1 in MCL cells Effects of fenofibrate on mantle cell lymphoma Z Zak et al blocks cell proliferation but is not sufficient to induce cell death in these cells. 35 Downregulation of cyclin D1 by PPARa agonist has been described in studies of human smooth muscle cells, 36 kidney cells 37 and cancer cells. 16,38 We decided to investigate whether fenofibrate has an effect on the regulation of cyclin D1.…”

Section: Minomentioning

confidence: 92%

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

2010

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Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin's lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-a (PPARa), can induce effective apoptosis in treating MCL cells. Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 lM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARa antagonist. Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-a (TNFa). Importantly, addition of recombinant TNF-a conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-jB-p65 and significantly inhibited the DNA binding of NF-jB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-a/NF-jB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.

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Section: Minomentioning

confidence: 92%

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

2010

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“…The presence of hypertension in STZ rats is controversial. In Zucker diabetic-fatty (ZDF) rats, changes in blood pressure were not observed at 7 weeks of age, but increases were observed after 13 weeks of age [13,20]. ZDF rats are considered to show hypertension with aging.…”

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confidence: 99%

Evaluation of Blood Pressure in Spontaneously Diabetic Torii-Leprfa Rats

et al. 2010

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Abstract:The Spontaneously Diabetic Torii-Lepr fa (SDT-fa/fa) rat, a new model of obese type 2 diabetes, shows obesity, hyperglycemia, and hyperlipidemia from 6 weeks of age. Diabetic complications such as nephropathy and cataract are observed with aging; however, blood pressure change with age has not previously been examined. In this study, blood pressure was periodically measured and the change was investigated. Blood pressure in male SDT-fa/fa rats was elevated at 8, 16, and 24 weeks of age, whereas the heart rate was not changed. In addition to hyperglycemia, hyperlipidemia, and proteinuria, hyperleptinemia and increased urine angiotensinogen were observed in SDT-fa/fa rats. Blood pressure and heart rate in the male original SDT (SDT-+/+) rat did not significantly change. In conclusion, the SDT-fa/fa rat is a promising model, showing significant hypertension with diabetes mellitus. Key words: blood pressure, diabetes, SDT-fa/fa rat (Received 8 February 2010 / Accepted 21 March 2010 Address corresponding: T. Ohta, Japan Tobacco Inc., Central Pharmaceutical Research Institute, 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan Cardiovascular diseases are major causes of death in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of cardiovascular disease. Hypertension, a common comorbid condition in dysmetabolic syndrome, often occurs in patients with type 2 diabetes, and vigorous control of blood pressure decreases the rate of cardiovascular events in such patients. Control of high blood pressure represents the most important intervention for such patients, limiting cardiovascular events more effectively than tight glycemic control [1,2,15]. Moreover, metabolic syndrome is defined worldwide as a lifestyle disease, and is described as a clustering of multiple metabolic abnormalities and cardiovascular risk factors, including hypertension, obesity, hyperlipidemia, and insulin resistance [3]. From these and other perspectives, it is an important to examine the relation between glycolipid abnormalities and blood pressure.The Spontaneously Diabetic Torii-Lepr fa (SDT-fa/fa) rat is a new model of obese type 2 diabetes, and was established by introducing the fa gene of the Zuckerfatty rat into the SDT rat genome [8]. SDT-fa/fa rats exhibit hyperphagia and obesity immediately after weaning, and diabetes and its complications are found at a younger age in SDT-fa/fa rats than in SDT-+/+ rats [4,9,10,12]. However, blood pressure in SDT-fa/fa rats has not yet been examined. In the present study, we periodically investigated the blood pressure of male -Note-

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“…16 PPARa is also well known as a determinant of the development of hypertension and renal damage, especially in AT-II-induced hypertensive rats. 21,23,24,30 Induction of the renal expression of CYP4A enzymes in the kidney using fibrate compounds has been reported to lower BP in SHR, stroke-prone SHR and Dahl salt-sensitive rats. 31,32 We found the inverse pattern of PPARa expression in kidneys of WKY-HF rats compared with that in SHR-HF animals.…”

Section: Discussionmentioning

confidence: 99%

“…It does so through NO production, oxidative stress and cytochrome P450-derived eicosanoids in the kidney. 23,24 Therefore, in this study, we investigated the role of fenofibrate on renal lipotoxicity associated with hypertension and renal inflammation using spontaneously hypertensive (SHR) rats fed a high-fat (HF) diet.…”

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

et al. 2009

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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.

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PPAR-Alpha Agonist Fenofibrate Induces Renal CYP Enzymes and Reduces Blood Pressure and Glomerular Hypertrophy in Zucker Diabetic Fatty Rats

Cited by 43 publications

References 79 publications

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

Evaluation of Blood Pressure in Spontaneously Diabetic Torii-Leprfa Rats

Peroxisome proliferator-activated receptor-α activator fenofibrate prevents high-fat diet-induced renal lipotoxicity in spontaneously hypertensive rats

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