Alterations of PPARalpha and its coactivator PGC-1 in cisplatin-induced acute renal failure

Portilla, Didier; Dai, Gonghe; McClure, Timothy; Bates, Linda M.; Kurten, Richard C.; Megyesi, Judit; Price, Peter W.; Li, Shenyang

doi:10.1046/j.1523-1755.2002.00553.x

Cited by 50 publications

(72 citation statements)

References 30 publications

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“…27 Several studies indicate that the AMPK, PPARa, and PGC1a pathways are important in fibrosis development. 29,[48][49][50][51] Data from the Duffield group suggest that microRNA 21 is an important upstream regulator of the pathway. 52 In conclusion, this study showed that selective deletion of Lkb1 in the kidney induced severe injury over time, characterized by dilated tubules and interstitial fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

109

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Renal tubule epithelial cells are high-energy demanding polarized epithelial cells. Liver kinase B1 (LKB1) is a key regulator of polarity, proliferation, and cell metabolism in epithelial cells, but the function of LKB1 in the kidney is unclear. Our unbiased gene expression studies of human control and CKD kidney samples identified lower expression of LKB1 and regulatory proteins in CKD. Mice with distal tubule epithelial-specific Lkb1 deletion (Ksp-Cre/Lkb1 flox/flox ) exhibited progressive kidney disease characterized by flattened dedifferentiated tubule epithelial cells, interstitial matrix accumulation, and dilated cystic-appearing tubules. Expression of epithelial polarity markers b-catenin and E-cadherin was not altered even at later stages. However, expression levels of key regulators of metabolism, AMP-activated protein kinase (Ampk), peroxisome proliferative activated receptor gamma coactivator 1-a (Ppargc1a), and Ppara, were significantly lower than those in controls and correlated with fibrosis development. Loss of Lkb1 in cultured epithelial cells resulted in energy depletion, apoptosis, less fatty acid oxidation and glycolysis, and a profibrotic phenotype. Treatment of Lkb1-deficient cells with an AMP-activated protein kinase (AMPK) agonist (A769662) or a peroxisome proliferative activated receptor alpha agonist (fenofibrate) restored the fatty oxidation defect and reduced apoptosis. In conclusion, we show that loss of LKB1 in renal tubular epithelial cells has an important role in kidney disease development by influencing intracellular metabolism. 27: 439-453, 201627: 439-453, . doi: 10.1681 Renal tubular epithelial cells (TECs) display strict apico-basal polarity. They allow a highly regulated uptake or excretion of substances at its apical surface, while keeping a closed, impenetrable surface through the formation of tight intercellular junctions in the basolateral membrane. The establishment and maintenance of TEC polarity is incompletely understood. The liver kinase B1 (LKB1) is an important regular of polarity. Early studies indicated that single intestinal epithelial cells polarize in a cell-autonomous fashion in response to LKB1 expression. 1 The LKB1 or STK11 gene encodes an evolutionarily conserved serine/threonine protein kinase. Following LKB1 expression, intestinal epithelial cells reorganized their cytoskeleton to form an apical brush border, demonstrating LKB1's critical role in establishing epithelial polarity. On the other hand, the effect of LKB1 on cell polarity appears to be cell type specific and deletion of LKB1 did not alter polarity of lung epithelial and pancreatic cells. 2 J Am Soc Nephrol

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Section: Discussionmentioning

confidence: 99%

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Han

Malaga-Dieguez

Chinga

et al. 2016

Journal of the American Society of Nephrology

109

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“…In addition to DNA damage, cisplatin inhibits fatty acid oxidation that is the main source of energy for the proximal tubule through reduction in PPAR-a mediated expression of genes involved in cellular fatty acid utilization. [21][22][23] Cisplatin also inhibits the mitochondrial complexes I to IV of the respiratory chain and induces decrease in intracellular ATP levels. 24 Creatine can prevent cell damage with two possible mechanisms: stabilization of cellular membranes and maintenance of ATP.…”

Section: Discussionmentioning

confidence: 99%

Effect of creatine and pioglitazone on Hk-2 cell line cisplatin nephrotoxicity

et al. 2014

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Cisplatin is a chemotherapeutic agent, which is used in the treatment of various solid organ cancers, and its main dose limiting side effect of cisplatin is nephrotoxicity. The aim of this study is to investigate the role of pioglitazone and creatine on cisplatin nephrotoxicity in vitro. Real-time cell analyzer system (RTCA) was used for real-time and time-dependent analysis of the cellular response of HK-2 cells following incubation with cisplatin and combination with creatine or pioglitazone hydrochloride. First, half-maximal inhibitory concentrations (IC50) of cisplatin, creatine and pioglitazone were calculated by RTCA system. Afterwards creatine and pioglitazone was administered with serial dilutions under RTCA system. IC50 dose for cisplatin was 7.69 M Â 10 À5 at 24th hour and 3.93 M Â 10 À6 at 48th hour. IC50 dose for pioglitazone was 1.61 M Â 10 À3 at 24th hour and 2.85 M Â 10 À4 at 48th hour. Although cells were treated the dose of 40,225 mM creatine, IC50 dose could not been reached. Neither pioglitazone nor creatine had additional protective effect in any dose. Consequently, beneficial effect of creatine and pioglitazone on cisplatin-induced cell death could not be found. Further studies and clinical trials are needed to evaluate the effect of different doses of these drugs in cisplatininduced nephrotoxicity.

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“…Furthermore, mitochondrial number is decreased after oxidative stress observed in models of ischemiareperfusion injury or from the cumulative oxidative stress associated with aging (Lemasters, 2005;Rasbach and Schnellmann, 2007b). Several disease models or toxicants decrease the expression of PGC-1␣ and are associated with impaired mitochondrial biogenesis (Portilla et al, 2002;Priault et al, 2005). Therefore, disease states or injury models associated with mitochondrial dysfunction and/or impaired biogenesis of mitochondria is therefore attractive targets for therapeutics aimed at stimulating the mitochondrial biogenesis pathway.…”

Section: Discussionmentioning

confidence: 99%

5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis

Rasbach

Funk²,

Jayavelu³

et al. 2009

J Pharmacol Exp Ther

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Mitochondrial dysfunction is both a cause and target of reactive oxygen species during ischemia-reperfusion, drug, and toxicant injury. After injury, renal proximal tubular cells (RPTC) recover mitochondrial function by increasing the expression of the master regulator of mitochondrial biogenesis, peroxisomeproliferator-activated-receptor-␥-coactivator-1␣ (PGC-1␣). The goal of this study was to determine whether 5-hydroxytryptamine (5-HT) receptor agonists increase mitochondrial biogenesis and accelerate the recovery of mitochondrial function. -193). In addition, DOI accelerated the recovery of mitochondrial function after oxidant-induced injury in RPTC. This is the first report to demonstrate 5-HT receptor-mediated mitochondrial biogenesis, and we suggest that 5-HT-agonists may be effective in the treatment of mitochondrial and cell injury.

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Alterations of PPARalpha and its coactivator PGC-1 in cisplatin-induced acute renal failure

Abstract: These results demonstrate that cisplatin deactivates PPARalpha by reducing its DNA binding activity and the availability of its tissue specific coactivator PGC-1.

Cited by 50 publications

References 30 publications

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

Effect of creatine and pioglitazone on Hk-2 cell line cisplatin nephrotoxicity

5-Hydroxytryptamine Receptor Stimulation of Mitochondrial Biogenesis

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