Differential effects of peroxisome proliferator activated receptor-γ (PPARγ) ligands in proximal tubular cells: Thiazolidinediones are partial PPARγ agonists

Chana, Ravinder S.; Lewington, Andrew; Brunskill, Nigel J.

doi:10.1111/j.1523-1755.2004.00624.x

Cited by 55 publications

(46 citation statements)

References 47 publications

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“…Administration of rosiglitazone and ciglitazone, two specific PPAR␥ agonists, have been shown to reduce renal dysfunction and injury associated with ischemia/reperfusion of the rat kidney (32). However, in sharp contrast to these in vivo experiments, PPAR␥ ligands have been shown to stimulate rather than prevent proximal tubular cell apoptosis in vitro, as did overexpression of PPAR␥ (31,33). PPAR␣ is also expressed in the convoluted part of the proximal tubule (15).…”

Section: Discussionmentioning

confidence: 83%

Peroxisome Proliferator-Activated Receptor β/δ Exerts a Strong Protection from Ischemic Acute Renal Failure

Letavernier

Perez

Joye

et al. 2005

Journal of the American Society of Nephrology

104

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Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPAR␤/␦ could contribute also to the control of tubular epithelium death after renal ischemia/ reperfusion was tested. It was found that PPAR␤/␦ ؉/؊ and PPAR␤/␦ ؊/؊ mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPAR␤/␦ ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na T he proximal straight tubule in the outer medulla of the kidney is particularly susceptible to ischemia/reperfusion injury, which remains the leading cause of acute renal failure (1,2). Damages to this segment are characterized initially by the disruption of tight junctions that control both paracellular permeability and cell polarity (3,4). The loss of cell polarity is responsible for the redistribution of integrin subunits from the basolateral to the apical membrane, contributing to the shedding of cells into the tubule lumen (4). Both increase in paracellular permeability and desquamation lead to back-leakage of glomerular filtrate (5). With more sustained ischemia/reperfusion, epithelial cells of the proximal tubule undergo necrotic or apoptotic cell death (6). Epithelial cells that do not die participate in the regeneration of tubular epithelium and the restoration of renal function (2,7). They use integrins to flatten, spread, and migrate into areas denuded by exfoliation, where they dedifferentiate, proliferate, and differentiate again (8).Peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦; called PPAR␤ hereafter) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor family (9). It plays a key role in cell survival (10 -14). For example, PPAR␤ activation leads to the expression of genes that increase the resistance of keratinocytes to apoptotic death (11,13). In these cells, PPAR␤ expression is also involved in the control of cell adhesion to the extracellular matrix and migration (10). All of these properties may account for the finding that PPAR␤ expression and activation participate in skin wound repair (10).By contrast with PPAR␣ and PPAR␥, PPAR␤ is ubiquitously expressed in all nephron segments within the kidney. In particular, it is the predominant PPAR isotype in the proximal straight tubule (15). Because of this high expression, we assessed whether PPAR␤ would contribute to the survival of proximal tubular cells in a model of ischemic acute renal failure. We found that PPAR␤-deficient mice were remarkably susc...

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Section: Discussionmentioning

confidence: 83%

Peroxisome Proliferator-Activated Receptor β/δ Exerts a Strong Protection from Ischemic Acute Renal Failure

Letavernier

Perez

Joye

et al. 2005

Journal of the American Society of Nephrology

104

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“…Collectively, these data suggest that PPAR-␥ may reverse the phenotypic change of mesangial cells, induce cell growth arrest, and decrease extracellular matrix accumulation in the diabetic condition. In addition to mesangial cells, PPAR-␥ expression was found recently to be expressed in the proximal tubular cells (182,183) and upregulated in the presence of high glucose (183). Activation of PPAR-␥ induces the G1 phase of cell-cycle arrest, and suppresses high glucose-induced AP-1 activity and MCP-1 expression in the proximal tubular cell line HK2 cells (183).…”

Section: Ppar-␥ and Diabetic Nephropathymentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome

Guan¹

2004

Journal of the American Society of Nephrology

158

129

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Abstract. Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligandactivated transcription factors. Three PPAR isoforms, designated PPAR␣, -␤/␦, and -␥, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-␣ activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-␥ agonists,

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“…Cell viability was analyzed using methylthiazoletetrazolium (MTT assay) as previously described (8).…”

Section: Methodsmentioning

confidence: 99%

Statin-sensitive endocytosis of albumin by glomerular podocytes

Eyre¹,

Ioannou²,

Grubb³

et al. 2007

American Journal of Physiology-Renal Physiology

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Whether podocytes are able to endocytose proteins is uncertain. We studied protein endocytosis in conditionally immortalized mouse and human podocytes using FITC-albumin by direct quantitative assay and by fluorescence microscopy and electron microscopy in mouse podocytes. Furthermore, in vivo uptake was studied in human, rat, and mouse podocytes. Both mouse and human podocytes displayed specific one-site binding for FITC-albumin with K d of 0.91 or 0.44 mg/ml and Bmax of 3.15 or 0.81 g/mg cell protein, respectively. In addition, they showed avid endocytosis of FITC-albumin with Km of 9.48 or 4.5 mg/ml and Vmax of 474.3 or 97.4 g⅐mg cell protein Ϫ1 ⅐h Ϫ1 , respectively. Immunoglobulin and transferrin were inefficient competitors of this process, indicating some specificity for albumin. Accumulation of endocytosed albumin could be demonstrated in intracellular vesicles by fluorescence confocal microscopy and electron microscopy. Endocytosis was sensitive to pretreatment with simvastatin.

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Differential effects of peroxisome proliferator activated receptor-γ (PPARγ) ligands in proximal tubular cells: Thiazolidinediones are partial PPARγ agonists

Abstract: PPAR gamma agonists exert differential effects in proximal tubule cells with thiazolidinediones behaving as partial agonists.

Cited by 55 publications

References 47 publications

Peroxisome Proliferator-Activated Receptor β/δ Exerts a Strong Protection from Ischemic Acute Renal Failure

Peroxisome Proliferator-Activated Receptor β/δ Exerts a Strong Protection from Ischemic Acute Renal Failure

Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome

Statin-sensitive endocytosis of albumin by glomerular podocytes

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