p66  Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells

Arany, István; Faisal, Amir; Nagamine, Yoshikuni; Safirstein, Robert

doi:10.1074/jbc.m708799200

Cited by 81 publications

(85 citation statements)

References 40 publications

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“…Earlier work of Safirstein, Heyman, Rosen, and others showed that the distal nephron can respond to a variety of injuries by expressing cytokines (114) and growth factors (115), activating ERK (116) and HIF (117), and redistributing corticomedullary circulation (118). Using mouse models, we showed that various injuries induce a cell-specific response in the CD, namely the activation of A-ICs (15).…”

Section: Figurementioning

confidence: 88%

α–Intercalated cells defend the urinary system from bacterial infection

Paragas¹,

Kulkarni²,

Werth³

et al. 2014

J. Clin. Invest.

129

111

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α-Intercalated cells (A-ICs) within the collecting duct of the kidney are critical for acid-base homeostasis. Here, we have shown that A-ICs also serve as both sentinels and effectors in the defense against urinary infections. In a murine urinary tract infection model, A-ICs bound uropathogenic E. coli and responded by acidifying the urine and secreting the bacteriostatic protein lipocalin 2 (LCN2; also known as NGAL). A-IC-dependent LCN2 secretion required TLR4, as mice expressing an LPS-insensitive form of TLR4 expressed reduced levels of LCN2. The presence of LCN2 in urine was both necessary and sufficient to control the urinary tract infection through iron sequestration, even in the harsh condition of urine acidification. In mice lacking A-ICs, both urinary LCN2 and urinary acidification were reduced, and consequently bacterial clearance was limited. Together these results indicate that A-ICs, which are known to regulate acid-base metabolism, are also critical for urinary defense against pathogenic bacteria. They respond to both cystitis and pyelonephritis by delivering bacteriostatic chemical agents to the lower urinary system.

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Section: Figurementioning

confidence: 88%

α–Intercalated cells defend the urinary system from bacterial infection

Paragas¹,

Kulkarni²,

Werth³

et al. 2014

J. Clin. Invest.

129

111

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“…Kidneys were removed and homogenized in a RIPA buffer as described earlier (2). Similarly, monolayers of cells were lysed in a RIPA buffer.…”

Section: Methodsmentioning

confidence: 99%

Chronic nicotine exposure exacerbates acute renal ischemic injury

Arany¹,

Grifoni

Clark³

et al. 2011

American Journal of Physiology-Renal Physiology

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Recent epidemiological reports showed that smoking has a negative impact on renal function and elevates the renal risk not only in the renal patient but perhaps also in the healthy population. Studies suggested that nicotine, a major tobacco alkaloid, links smoking to renal dysfunction. While several studies showed that smoking/chronic nicotine exposure exacerbates the progression of chronic renal diseases, its impact on acute kidney injury is virtually unknown. Here, we studied the effects of chronic nicotine exposure on acute renal ischemic injury. We found that chronic nicotine exposure increased the extent of renal injury induced by warm ischemia-reperfusion as evidenced by morphological changes, increase in plasma creatinine level, and kidney injury molecule-1 expression. We also found that chronic nicotine exposure elevated markers of oxidative stress such as nitrotyrosine as well as malondialdehyde. Interestingly, chronic nicotine exposure alone increased oxidative stress and injury in the kidney without morphological alterations. Chronic nicotine treatment not only increased reactive oxygen species (ROS) production and injury but also exacerbated oxidative stress-induced ROS generation through NADPH oxidase and mitochondria in cultured renal proximal tubule cells. The resultant oxidative stress provoked injury through JNK-mediated activation of the activator protein (AP)-1 transcription factor in vitro. This mechanism might exist in vivo as phosphorylation of JNK and its downstream target c-jun, a component of the AP-1 transcription factor, is elevated in the ischemic kidneys exposed to chronic nicotine. Our results imply that smoking may sensitize the kidney to ischemic insults and perhaps facilitates progression of acute kidney injury to chronic kidney injury.

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“…Accordingly, in this study, overexpression of a phosphorylation-defective p66 Shc mutant protein in INS-1E cells did not affect basal and reduced palmitate-induced apoptosis, respectively. Depending on the cellular context and stimulus, Ser 36 phosphorylation of p66 Shc was found to be promoted by either the MAP kinases ERK-1/2 or the stressactivated kinases JNK and p38 MAPK [14,15,35,[38][39][40][41][42]. In specific cells, it was shown to be mediated by PKCβ activation [43][44][45].…”

Section: Discussionmentioning

confidence: 95%

“…p66 Shc possesses specific functions, such as modulation of p46/52 Shc complex activation and downstream signalling via MAPK kinase (MEK)-extracellular signal-regulated kinase (ERK) [13][14][15][16] and control of actin cytoskeleton turnover and glucose transport [16,17]. Importantly, p66 Shc is implicated in both sensing and activation of cellular oxidative stress and consequent induction of apoptosis [18].…”

Section: Introductionmentioning

confidence: 99%

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

et al. 2015

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Aims/hypothesis The role of the redox adaptor protein p66 Shc as a potential mediator of saturated fatty acid (FA)-induced beta cell death was investigated. Methods The effects of the FA palmitate on p66 Shc expression were evaluated in human and murine islets and in rat insulinsecreting INS-1E cells. p66 Shc expression was also measured in islets from mice fed a high-fat diet (HFD) and from human donors with different BMIs. Cell apoptosis was quantified by two independent assays. The role of p66 Shc was investigated using pancreatic islets from p66 Shc−/− mice and in INS-1E cells with knockdown of p66 Shc or overexpression of wildtype and phosphorylation-defective p66 Shc . Production of reactive oxygen species (ROS) was evaluated by the dihydroethidium oxidation method. Results Palmitate induced a selective increase in p66 Shc protein expression and phosphorylation on Ser 36 and augmented apoptosis in human and mouse islets and in INS-1E cells. Inhibiting the tumour suppressor protein p53 prevented both the palmitate-induced increase in p66 Shc expression and beta cell apoptosis. Palmitate-induced apoptosis was abrogated in islets from p66 Shc−/− mice and following p66 Shc knockdown in INS-1E cells; by contrast, overexpression of p66 Shc , but not that of the phosphorylation-defective p66 Shc mutant, enhanced palmitate-induced apoptosis. The pro-apoptotic effects of p66 Shc were dependent upon its c-Jun N-terminal kinasemediated phosphorylation on Ser 36 and associated with generation of ROS. p66 Shc protein expression and function were also elevated in islets from HFD-fed mice and from obese/ overweight cadaveric human donors. Conclusions/interpretation p53-dependent augmentation of p66 Shc expression and function represents a key signalling response contributing to beta cell apoptosis under conditions of lipotoxicity.

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p66 Inhibits Pro-survival Epidermal Growth Factor Receptor/ERK Signaling during Severe Oxidative Stress in Mouse Renal Proximal Tubule Cells

Cited by 81 publications

References 40 publications

α–Intercalated cells defend the urinary system from bacterial infection

α–Intercalated cells defend the urinary system from bacterial infection

Chronic nicotine exposure exacerbates acute renal ischemic injury

The p66Shc redox adaptor protein is induced by saturated fatty acids and mediates lipotoxicity-induced apoptosis in pancreatic beta cells

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