Activation of Epidermal Growth Factor Receptor in the Early Phase after Renal Ischemia-Reperfusion in Rat

Yano, Tomohiro; Yazima, Shoko; Hagiwara, Kiyokazu; Ozasa, Hisashi; Ishizuka, Shino; Horikawa, Saburo

doi:10.1159/000045281

Cited by 26 publications

(19 citation statements)

References 15 publications

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“…The EGFR is capable of activating a series of signaling pathways that may be involved in regulating PGC-1␣ expression, including phosphatidylinositol 3-kinase (34,42). However, inhibition of phosphatidylinositol 3-kinase/Akt had no effect on the expression of PGC-1␣ following oxidant exposure.…”

Section: Discussionmentioning

confidence: 99%

Signaling of Mitochondrial Biogenesis following Oxidant Injury

Rasbach¹,

Schnellmann

2007

Journal of Biological Chemistry

142

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Mitochondrial dysfunction is a common consequence of ischemia-reperfusion and drug injuries. For example, sublethal injury of renal proximal tubular cells (RPTCs) with the model oxidant tert-butylhydroperoxide (TBHP) causes mitochondrial injury that recovers over the course of six days. Although regeneration of mitochondrial function is integral to cell repair and function, the signaling pathway of mitochondrial biogenesis following oxidant injury has not been examined. A 10-fold overexpression of the mitochondrial biogenesis regulator PPAR-␥ cofactor-1␣ (PGC-1␣) in control RPTCs resulted in a 52% increase in mitochondrial number, a 27% increase in respiratory capacity, and a 30% increase in mitochondrial protein markers, demonstrating that PGC-1␣ mediates mitochondrial biogenesis in RPTCs. RPTCs sublethally injured with TBHP exhibited a 50% decrease in mitochondrial function and increased mitochondrial autophagy. Compared with the controls, PGC-1␣ levels increased 12-fold on days 1, 2, and 3 post-injury and returned to base line on day 4 as mitochondrial function returned. Inhibition p38 MAPK blocked the up-regulation of PGC-1␣ following oxidant injury, whereas inhibition of calcium-calmodulindependent protein kinase, calcineurin A, nitric-oxide synthase, and phosphoinositol 3-kinase had no effect. The epidermal growth factor receptor (EGFR) was activated following TBHP exposure, and the EGFR inhibitor AG1478 blocked the up-regulation of PGC-1␣. Additional inhibitor studies revealed that the sequential activation of Src, p38 MAPK, EGFR, and p38 MAPK regulate the expression of PGC-1␣ following oxidant injury. In contrast, although Akt was activated following oxidant injury, it did not play a role in PGC-1␣ expression. We suggest that mitochondrial biogenesis following oxidant injury is mediated by p38 and EGFR activation of PGC-1␣.3 is a 92-kDa protein that was first identified as a regulator of adaptive thermogenesis in brown adipose tissue (1). PGC-1␣ is highly expressed in tissues with high metabolic demands, such as heart, skeletal muscle, and kidney (1). Ectopic expression of PGC-1␣ was later shown to stimulate the biogenesis of mitochondria by increasing the expression of nuclear respiratory factors 1 and 2 and enhancing the transcriptional activity of nuclear respiratory factor 1 on the promoter for mitochondrial transcription factor A (1). In addition to cold exposure, expression of PGC-1␣ is responsive to various physiological stimuli, such as exercise, caloric restriction, and exposure to lipopolysaccharide (1-4), demonstrating the ability of PGC-1␣ to alter the metabolic state of the cell in response to changes in the cellular or extracellular environment. What has not been examined is the signaling pathway responsible for mitochondrial biogenesis following cellular and mitochondrial injury, particularly oxidative stress.A variety of signaling mechanisms have been proposed to regulate the expression of PGC-1␣ and mitochondrial biogenesis including nitric oxide-soluble guanylate cyclase (5-12), ␤-adren...

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Section: Discussionmentioning

confidence: 99%

Signaling of Mitochondrial Biogenesis following Oxidant Injury

Rasbach¹,

Schnellmann

2007

Journal of Biological Chemistry

142

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“…The remaining epithelial cells after injury may receive multiple signals to initiate proliferation. The oxidant exposure from the ischemia-reperfusion may directly activate Src or the EGF receptor (29,34,41). In addition, a signal may result from autocrine/paracrine mechanisms in which a growth factor is released locally and binds to a growth factor receptor.…”

Section: Discussionmentioning

confidence: 99%

Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms

Xing¹,

Zhu²,

Mao³

et al. 2008

American Journal of Physiology-Renal Physiology

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Xing J, Zhang Z, Mao H, Schnellmann RG, Zhuang S. Src regulates cell cycle protein expression and renal epithelial cell proliferation via PI3K/Akt signaling-dependent and -independent mechanisms. Am J Physiol Renal Physiol 295: F145-F152, 2008. First published April 23, 2008 doi:10.1152/ajprenal.00092.2008.-Our recent studies showed that Src family kinases (SFKs) are important mediators of proliferation in renal proximal tubular cells (RPTC). In this study, we elucidate the signaling mechanisms that mediate SFK regulation of cell proliferation and cycle protein expression, and identify the SFK member responsible for these responses in a mouse RPTC line. Akt, a target of phosphoinositide-3-kinase (PI3K), and ERK1/2 were constitutively phosphorylated in RPTC cultured in the presence of serum. While treatment of cells with PP1, a specific SFK inhibitor, completely blocked phosphorylation of ERK1/2 and Akt, only inhibition of PI3K/Akt resulted in decreased RPTC proliferation. Incubation of cells with PP1 decreased cyclin D1 expression, decreased p27 and p57 phosphorylation, and increased p27 and p57 expression, two cyclin-dependent kinase inhibitors. Inhibition of the PI3K pathway decreased expression of cyclin D1 without altering expression of p27 and p57. In contrast, PP1 and PI3K inhibition had no effect on cyclin E and p21. Although RPTC expressed Src, Fyn, and Lyn, only siRNA-mediated knockdown of Src decreased RPTC proliferation, decreased cyclin D1 expression, and increased p27 and p57 expression. These data reveal that Src is a crucial mediator of RPTC proliferation and Src-mediated proliferation is associated with PI3K-dependent upregulation of cyclin D1 and PI3K-independent downregulation of p27 and p57.

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“…EGFR gene expression, abundance of EGFR ligands, and EGFR activation have all been shown to increase in a variety of models of experimental acute kidney injury, including ischemia and reperfusion injury (14,15,21,38,50). Administration of exogenous EGFR ligands has also been shown to accelerate recovery from ischemic acute kidney injury (17,29).…”

mentioning

confidence: 99%