Actin cytoskeleton in ischemic acute renal failure

Molitoris, Bruce A.

doi:10.1111/j.1523-1755.2004.00818.x

Cited by 75 publications

(54 citation statements)

References 98 publications

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“…Along with this hypothesis, spe- cific PPAR␤ ligands have been shown to inhibit the expression of proinflammatory cytokines (e.g., monocyte chemoattractant protein-1) in both macrophages and endothelial cells (27,28). Because vascular endothelium activation and injury contribute to reduce renal perfusion and, hence, to decrease GFR (29,30), PPAR␤ ligands would protect renal function by preventing these mechanisms as well.…”

Section: Discussionmentioning

confidence: 99%

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

102

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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: 99%

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

102

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“…Increasing the duration of ischemia results in worse cell injury, reduced function, and longer recovery periods (42,43). Pioneering work in rats using the renal artery clamp model revealed that PTCs recovered rapidly and completely following mild ischemia via cellular repair.…”

Section: Proximal Tubule Cellsmentioning

confidence: 99%

Therapeutic translation in acute kidney injury: the epithelial/endothelial axis

Molitoris¹

2014

J. Clin. Invest.

Self Cite

176

204

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“…16 These changes occur very rapidly, correlate with the severity and duration of experimental AKI, and are important for the structural and functional integrity of renal proximal tubule cells, endothelial cells, and vascular smooth muscle cells during AKI. Alterations in the actin cytoskeleton regulate changes in cell polarity, cell-cell interactions, and cell-matrix interactions, and, as a result, influence the GFR and tubular function.…”

Section: Cytoskeletonmentioning

confidence: 99%

Cellular and Molecular Mechanisms of AKI

Agarwal

Dong

Harris

et al. 2016

JASN

175

151

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In this article, we review the current evidence for the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, using ischemic AKI as a model. Highlighted are the clinical relevance of cellular and molecular targets that have been investigated in experimental models of ischemic AKI and how such models might be improved to optimize translation into successful clinical trials. In particular, development of more context-specific animal models with greater relevance to human AKI is urgently needed. Comorbidities that could alter patient susceptibility to AKI, such as underlying diabetes, aging, obesity, cancer, and CKD, should also be considered in developing these models. Finally, harmonization between academia and industry for more clinically relevant preclinical testing of potential therapeutic targets and better translational clinical trial design is also needed to achieve the goal of developing effective interventions for AKI. Cellular and molecular mechanisms of AKI have been extensively investigated in a variety of experimental models, through which a number of candidate therapies for AKI have been identified. This article reviews the current evidence by dissecting the cellular and molecular mechanisms of AKI, focusing on epithelial cell pathobiology and related cell-cell interactions, and using the example of ischemic AKI to describe our approach. Specifically, we reviewed the cellular and molecular epithelial cell targets that have been investigated in experimental models of ischemic AKI, and considered the clinical relevance of these models in human AKI and how such models might be improved to optimize translation into successful clinical trials. We have structured our review to answer two key questions:

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Actin cytoskeleton in ischemic acute renal failure

Cited by 75 publications

References 98 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

Therapeutic translation in acute kidney injury: the epithelial/endothelial axis

Cellular and Molecular Mechanisms of AKI

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