Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPARα/γ), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats

Liao, Jie; Soltani, Zohreh; Ebenezer, Philip J.; Isidro-Carrión, Angel A.; Zhang, Rubin; Asghar, Arshad; Aguilar, Erwin A.; Francis, Joseph; Hu, Xuejiao; Ferder, León; Reisin, Efrain

doi:10.1159/000254567

Cited by 14 publications

(9 citation statements)

References 70 publications

(57 reference statements)

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“…Conversely, starved PPAR α null mice would show increased albuminuria with albumin accumulation in the proximal tubules further confirming the beneficial role of PPAR- α [33]. Therefore, it is likely that PPAR α activation may facilitate albumin reabsorption and degradation in the nephron segment [34, 35]. Taken together, fenofibrate treatment activated PPAR α may reduce TGF- β -induced proliferation in mesangial cells, thus ameliorate kidney injury.…”

Section: Pparα and Kidney Mesangial Cellsmentioning

confidence: 95%

Role of PPARαand Its Agonist in Renal Diseases

2010

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Peroxisome proliferator-activated receptor (PPAR)-α, a member of a large nuclear receptor superfamily, plays a major role in the regulation of lipid metabolism. Recently, PPARα activation has been shown to confer additional benefits on endothelial function, kidney function, and anti-inflammation, suggesting that PPARα agonists may be good candidates for treating acute renal failure. In clinical application, PPAR-α activators, such as hypolipidemic drugs in fibric acid class, were proven to have therapeutic effects on metabolic syndrome and cardiovascular disease. This paper focuses on signaling pathways, ligand selectivity, and physio-pathological roles of PPARα in kidney diseases and the therapeutic utility of PPARα modulators in the treatment of diabetes and inflammation-induced nephropathy. Implication of new and more potent PPAR-α activators could provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and the prevention of diabetic or inflammation-induced nephropathy in the future.

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Section: Pparα and Kidney Mesangial Cellsmentioning

confidence: 95%

Role of PPARαand Its Agonist in Renal Diseases

2010

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“…249 Muraglitazar prevents the onset of diabetes and its complications in db/db mice 250 and reduces hemoglobin A 1C and improves lipid profiles in diabetic patients. 251 Another dual PPAR modulator, tesaglitazar, reduces atherosclerosis in mice with LDL receptor deficiency, 252 improves metabolic abnormalities and renal function, decreases blood pressure, and prevents glomerular and interstitial lesions in obese Zucker rats 253 and db/db mice. 254 Tesaglitazar suppresses both hyperglycemia and dyslipidemia in diabetic patients.…”

Section: Pharmacologic Treatmentsmentioning

confidence: 99%

Role of Lipotoxicity in Endothelial Dysfunction

Kim¹,

Montagnani²,

Chandrasekran³

et al. 2012

Heart Failure Clinics

107

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SUMMARY Lipotoxicity, caused in large part by overnutrition, directly leads to endothelial dysfunction. Excess lipids in both the circulation and at the tissue level contribute to endothelial dysfunction that underlies much of the pathophysiology of both metabolic disease, including obesity and diabetes and their CV complications. Direct lipotoxic effects on other organs as well as secondary insults from endothelial dysfunction synergize to cause substantial morbidity and mortality. Lifestyle interventions, including reduced calorie intake, diet, and exercise as well as a variety of pharmacologic interventions targeting various mechanisms underlying lipotoxicity in vascular endothelium significantly modify metabolic and CV risk.

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“…It is hoped that these agents will combine the beneficial properties of thiazolidinediones and fibrates in one chemical structure Schuster et al, 2008;Henry et al, 2009). Two of these dual agents have already been reported to lower blood pressure in hypertensive animals (Mamnoor et al, 2006;Liao et al, 2009). Mechanisms responsible for this action have not been identified.…”

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionsmentioning

confidence: 99%

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Phelps

Peuler

2010

J. Smooth Muscle Res.

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Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPARα may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 μM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 μM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or spontaneously-occurring. These findings are particularly relevant to both the recently renewed concern over the impact of fibrates on hypertension and a new understanding of their gastrointestinal side effects.

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Tesaglitazar, a Dual Peroxisome Proliferator- Activated Receptor Agonist (PPARα/γ), Improves Metabolic Abnormalities and Reduces Renal Injury in Obese Zucker Rats

Cited by 14 publications

References 70 publications

Role of PPARαand Its Agonist in Renal Diseases

Role of PPARαand Its Agonist in Renal Diseases

Role of Lipotoxicity in Endothelial Dysfunction

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

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