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Ppar alpha AND nephropathy

Yanli Cheng, Jingjing Zhang, Weiying Guo, Fengsheng Li, Weixia Sun, Jing Chen, Chi Zhang, Xuemian Lu, Yi Tan, Wenke Feng, Yaowen Fu, Gilbert C Liu, Zhonggao Xu, Lu Cai
The lipid lowering medication, fenofibrate (FF), is a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, possessing beneficial effects for type 2 diabetic nephropathy (DN). We investigated whether FF can prevent the development of type 1 DN, and the underlying mechanisms. Diabetes was induced by a single intraperitoneal injection of streptozotocin in C57BL/6J mice. Mice were treated with oral gavage of FF at 100mg/kg every other day for 3 and 6 months. Diabetes-induced renal oxidative stress, inflammation, apoptosis, lipid and collagen accumulation, and renal dysfunction were accompanied by significant decrease in PI3K, Akt, and GSK-3β phosphorylation as well as an increase in the nuclear accumulation of Fyn [a negative regulator of nuclear factor (erythroid-derived 2)-like 2 (Nrf2)]...
April 2016: Free Radical Biology & Medicine
Chunyang Du, Yonghong Shi, Yunzhuo Ren, Haijiang Wu, Fang Yao, Jinying Wei, Ming Wu, Yanjuan Hou, Huijun Duan
The dysregulation of cholesterol metabolism and inflammation plays a significant role in the progression of diabetic nephropathy (DN). Anthocyanins are polyphenols widely distributed in food and exert various biological effects including antioxidative, anti-inflammatory, and antihyperlipidemic effects. However, it remains unclear whether anthocyanins are associated with DN, and the mechanisms involved in the reciprocal regulation of inflammation and cholesterol efflux are yet to be elucidated. In this study, we evaluated the regulation of cholesterol metabolism and the anti-inflammatory effects exerted by anthocyanins (cyanidin-3-O-β-glucoside chloride [C3G] or cyanidin chloride [Cy]) and investigated the underlying molecular mechanism of action using high-glucose (HG)-stimulated HK-2 cells...
2015: Drug Design, Development and Therapy
Luis Ruilope, Markolf Hanefeld, A Michael Lincoff, Giancarlo Viberti, Sylvie Meyer-Reigner, Nadejda Mudie, Dominika Wieczorek Kirk, Klas Malmberg, Matthias Herz
BACKGROUND: Type 2 diabetes is a major risk factor for chronic kidney disease, which substantially increases the risk of cardiovascular disease mortality. This Phase IIb safety study (AleNephro) in patients with stage 3 chronic kidney disease and type 2 diabetes, evaluated the renal effects of aleglitazar, a balanced peroxisome proliferator-activated receptor-α/γ agonist. METHODS: Patients were randomized to 52 weeks' double-blind treatment with aleglitazar 150 μg/day (n=150) or pioglitazone 45 mg/day (n=152), followed by an 8-week off-treatment period...
2014: BMC Nephrology
Neelamegam Kandasamy, Natarajan Ashokkumar
Myricetin is a natural flavonoid used in various health management systems. In this present study myricetin tested to evaluate the effect on lipids and lipid metabolism enzymes in normal and streptozotocin (STZ) with cadmium (Cd) induced diabetic nephrotoxic rats. Diabetic nephrotoxic rats were significantly (P<0.05) increased the levels of urinary albumin and lipid profiles: total cholesterol (TC), triglycerides (TGs), free fatty acids (FFAs), phospholipids (PLs), low density lipoprotein (LDL), very low-density lipoproteins (VLDL), and decreased in the levels of high-density lipoproteins (HDL)...
November 15, 2014: European Journal of Pharmacology
Wan-Ju Yeh, Hsin-Yi Yang, Jiun-Rong Chen
Soy protein was known to have renal-protective effects. The aim of this study was to investigate the effects of different doses of soybean β-conglycinin, one of the main storage proteins in soy, on diabetic nephropathy in the rat. We used 40 Wistar rats with eight rats in each group. Diabetes mellitus was induced in rats by an intravenous injection of streptozotocin. The groups included a control group (Ctrl) fed with the standard AIN93-M diet, while other groups were fed with AIN-93M with the addition of NaCl to induce diabetic nephropathy (DN)...
November 2014: Food & Function
Bardia Askari, Tomasz Wietecha, Kelly L Hudkins, Edward J Fox, Kevin D O'Brien, Jinkyu Kim, Tri Q Nguyen, Charles E Alpers
Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus...
August 2014: Laboratory Investigation; a Journal of Technical Methods and Pathology
Xueying Zhao, Yuanyuan Zhang, Michelle Leander, Lingyun Li, Guoshen Wang, Nerimiah Emmett
Alpha(1D)-adrenergic receptor (α(1D)-AR) plays important roles in regulating physiological and pathological responses mediated by catecholamines, particularly in the cardiovascular and urinary systems. The present study was designed to investigate the expression profile of α(1D)-AR in the diabetic kidneys and its modulation by activation of peroxisome proliferator-activated receptors (PPARs). 12-week-old Zucker lean (ZL) and Zucker diabetic fatty (ZD) rats were treated with fenofibrate or rosiglitazone for 8-10 weeks...
2014: Journal of Diabetes Research
Daniela Impellizzeri, Emanuela Esposito, James Attley, Salvatore Cuzzocrea
Chronic inflammation and oxidative stress, features that are closely associated with nuclear factor (NF-κB) activation, play a key role in the development and progression of chronic kidney disease (CKD). Several animal models and clinical trials have clearly demonstrated the effectiveness of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy to improve glomerular/tubulointerstitial damage, reduce proteinuria, and decrease CKD progression, but CKD treatment still represents a clinical challenge...
March 2014: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Michal Herman-Edelstein, Pnina Scherzer, Ana Tobar, Moshe Levi, Uzi Gafter
Animal models link ectopic lipid accumulation to renal dysfunction, but whether this process occurs in the human kidney is uncertain. To this end, we investigated whether altered renal TG and cholesterol metabolism results in lipid accumulation in human diabetic nephropathy (DN). Lipid staining and the expression of lipid metabolism genes were studied in kidney biopsies of patients with diagnosed DN (n = 34), and compared with normal kidneys (n = 12). We observed heavy lipid deposition and increased intracellular lipid droplets...
March 2014: Journal of Lipid Research
Rui Zeng, Yan Xiong, Fengming Zhu, Zufu Ma, Wenhui Liao, Yong He, JinSeng He, Wei Li, Juan Yang, Qian Lu, Gang Xu, Ying Yao
Excess mesangial extracellular matrix (ECM) and mesangial cell proliferation is the major pathologic feature of diabetic nephropathy (DN). Fenofibrate, a PPARα agonist, has been shown to attenuate extracellular matrix formation in diabetic nephropathy. However, the mechanisms underlying this effect remain to be elucidated. In this study, the effect of fenofibrate on high-glucose induced cell proliferation and extracellular matrix exertion and its mechanisms were investigated in cultured rat mesangial cells by the methylthiazoletetrazolium (MTT) assay, flow cytometry and western blot...
2013: PloS One
Soundarya L Madhira, Satya S Challa, Maniprabha Chalasani, Giridharan Nappanveethl, Ramesh R Bhonde, Rajanna Ajumeera, Vijayalakshmi Venkatesan
BACKGROUND: Development of model systems have helped to a large extent, in bridging gap to understand the mechanism(s) of disease including diabetes. Interestingly, WNIN/GR-Ob rats (Mutants), established at National Centre for Laboratory Animals (NCLAS) of National Institute of Nutrition (NIN), form a suitable model system to study obesity with Type 2 diabetes (T2D) demonstrating several secondary complications (cataract, cardiovascular complications, infertility, nephropathy etc). The present study has been carried out to explore the potent application(s) of multipotent stem cells such as bone marrow mesenchymal stem cells (BM-MSCs), to portray features of pre-diabetic/T2D vis-à-vis featuring obesity, with impaired glucose tolerance (IGT), hyperinsulinemia (HI) and insulin resistance (IR) seen with Mutant rats akin to human situation...
2012: PloS One
A Bénardeau, P Verry, E-A Atzpodien, J M Funk, M Meyer, J Mizrahi, M Winter, M B Wright, S Uhles, E Sebokova
AIMS: To evaluate the effects of aleglitazar, a dual peroxisome proliferator-activated receptor-α/γ agonist, on the development of diabetes-related organ dysfunction, in relation to glycaemic and lipid changes, in Zucker diabetic fatty (ZDF) rats. METHODS: Six-week-old, male ZDF rats received aleglitazar 0.3 mg/kg/day or vehicle as food admix for 13 weeks (n = 10 per group). Age-matched male Zucker lean rats served as non-diabetic controls. Plasma and renal markers were measured at several time points...
February 2013: Diabetes, Obesity & Metabolism
Harish Kumar Bishnoi, Nanjaian Mahadevan, Pitchai Balakumar
We have previously shown that the low-dose combination of fenofibrate and rosiglitazone might halt the progression of diabetes-induced nephropathy in rats. The present study investigated the combined effect of fenofibrate (PPARα agonist) and telmisartan (AT₁ receptor antagonist) in diabetes-induced onset of nephropathy in rats. The single administration of streptozotocin (STZ, 55 mg/kg i.p.) produced diabetes mellitus, which subsequently produced nephropathy in 8 weeks by markedly elevating serum creatinine, blood urea nitrogen and microproteinuria...
October 2012: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
I Kouroumichakis, N Papanas, P Zarogoulidis, V Liakopoulos, E Maltezos, D P Mikhailidis
Despite intensive glucose-lowering treatment and advanced therapies for cardiovascular risk factors, such as hypertension and dyslipidaemia, diabetes mellitus with its macro- and microvascular complications remains a major health problem. Especially diabetic nephropathy is a leading cause of morbidity and mortality, and its prevalence is increasing. Peroxisome proliferator-activated receptor-α (PPAR-α), a member of a large nuclear receptor superfamily, is expressed in several tissues including the kidney...
June 2012: European Journal of Internal Medicine
Pitchai Balakumar, Supriya Kadian, Nanjaian Mahadevan
The uncontrolled diabetes mellitus may result in the induction of diabetic nephropathy, one of the detrimental microvascular complications of diabetes mellitus. Diabetic nephropathy is associated with glomerular hypertrophy, glomerulosclerosis, tubulointerstitial fibrosis, mesangial cell expansion, followed by albuminuria and reduction in glomerular filtration rate. Indeed, no promising therapeutic options are available in the present clinical scenario to manage efficiently the diabetic nephropathy. Nevertheless, angiotensin converting enzyme inhibitors and angiotensin-II-AT(1) receptor blockers are currently employed to improve structural and functional status of the diabetic kidney...
April 2012: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Haitao Zhang, Xing Xu, Lili Chen, Jing Chen, Lihong Hu, Hualiang Jiang, Xu Shen
Nuclear receptors retinoic X receptor α (RXRα) and peroxisome proliferator activated receptor γ (PPARγ) function potently in metabolic diseases, and are both important targets for anti-diabetic drugs. Coactivation of RXRα and PPARγ is believed to synergize their effects on glucose and lipid metabolism. Here we identify the natural product magnolol as a dual agonist targeting both RXRα and PPARγ. Magnolol was previously reported to enhance adipocyte differentiation and glucose uptake, ameliorate blood glucose level and prevent development of diabetic nephropathy...
2011: PloS One
Kadiombo Bantubungi, Janne Prawitt, Bart Staels
Today, we are witnessing a rising incidence of obesity worldwide. This increase is due to a sedentary life style, an increased caloric intake and a decrease in physical activity. Obesity contributes to the appearance of type 2 diabetes, dyslipidemia and cardiovascular complications due to atherosclerosis, and nephropathy. Therefore, the development of new therapeutic strategies may become a necessity. Given the metabolism controlling properties of nuclear receptors in peripheral organs (such as liver, adipose tissues, pancreas) and their implication in various processes underlying metabolic diseases, they constitute interesting therapeutic targets for obesity, dyslipidemia, cardiovascular disease and type 2 diabetes...
July 2012: Journal of Steroid Biochemistry and Molecular Biology
Sungjin Chung, Cheol Whee Park
With a developing worldwide epidemic of diabetes mellitus, the renal complications associated with diabetes have become a serious health concern. Primary therapy for treating diabetic nephropathy is a multifactorial process. Peroxisome proliferator-activated receptor alpha (PPARα) agonists have been used primarily in clinical practice for the treatment of dyslipidemia and insulin resistance. Given that PPARα expression and regulation of metabolic pathways are involved in oxidative stress, inflammation, blood pressure regulation, and the renin-angiotensin aldosterone system, PPARα likely influences the development and pathogenesis of diabetic nephropathy via indirect effects on glucose and lipid homeostasis and also by direct action on the kidneys...
August 2011: Diabetes & Metabolism Journal
Xu Yang, Shinji Kume, Yuki Tanaka, Keiji Isshiki, Shin-ichi Araki, Masami Chin-Kanasaki, Toshiro Sugimoto, Daisuke Koya, Masakazu Haneda, Takeshi Sugaya, Detian Li, Ping Han, Yoshihiko Nishio, Atsunori Kashiwagi, Hiroshi Maegawa, Takashi Uzu
Peroxisome proliferator-activated receptors (PPARs) are a nuclear receptor family of ligand-inducible transcription factors, which have three different isoforms: PPARα, δ and γ. It has been demonstrated that PPARα and γ agonists have renoprotective effects in proteinuric kidney diseases; however, the role of PPARδ agonists in kidney diseases remains unclear. Thus, we examined the renoprotective effect of GW501516, a PPARδ agonist, in a protein-overload mouse nephropathy model and identified its molecular mechanism...
2011: PloS One
Kiyoshi Mori, Masashi Mukoyama, Kazuwa Nakao
Immunosuppressants and inhibitors of the renin angiotensin system are major reagents to treat nephrotic syndrome but their clinical effects are not necessarily satisfactory. Injection of doxorubicin in several strains of mice causes nephrotic syndrome-like disorder. Zhou et al. report that PPAR-α expression is downregulated in murine doxorubicin nephropathy and a PPAR-α agonist, fenofibrate, partially ameliorates the disorder induced likely through stabilization of nephrin expression and suppression of apoptosis in podocytes, providing a new preventive strategy...
June 2011: Kidney International
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