Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

Collier, Justin B.; Whitaker, Ryan M.; Eblen, Scott T.; Schnellmann, Rick G.

doi:10.1074/jbc.m116.754762

Cited by 28 publications

(25 citation statements)

References 43 publications

(60 reference statements)

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“…2, C and D). Trametinib also completely inhibited ERK1/2 phosphorylation increases following AKI, as observed previously (Smith et al, 2015;Collier et al, 2016). Ajay et al (2014) reported that Chk1 phosphorylation is elevated 3 hours post IR AKI.…”

Section: Earlysupporting

confidence: 84%

“…Different superscripts indicate statistically significant differences (P , 0.05). (Smith et al, 2015(Smith et al, , 2016Collier et al, 2016). Here, ERK1/2 involvement with STAT3 after renal injury was observed.…”

Section: Discussionmentioning

confidence: 61%

“…Mouse tissue nuclear and cytosolic fraction lysates were prepared as previously described (Collier et al, 2016). Briefly, a piece of kidney cortex was homogenized in sucrose isolation buffer (250 mM sucrose, 1 mM EGTA, 10 mM HEPES, 1 mg/ml fatty acid-free bovine serum albumin, pH 7.4) added fresh with a dounce tissue grinder.…”

Section: Methodsmentioning

confidence: 99%

“…Extracellular signal-regulated kinase 1/2 (ERK1/2) is a mitogen-activated protein kinase that is phosphorylated rapidly following renal injury (Masaki et al, 2003(Masaki et al, , 2004Arany et al, 2004). We previously demonstrated ERK1/2 phosphorylation is elevated 3 hours post IR injury and 1 hour post lipopolysaccharide (LPS)-induced acute kidney injury (AKI) (Smith et al, 2015;Collier et al, 2016). Further exploration of the ERK1/2 pathway was performed utilizing a specific mitogen-activated protein kinase kinase 1/2 inhibitor, trametinib, which inhibits the increase in ERK1/2 phosphorylation since mitogen-activated protein kinase kinase 1/2 is directly upstream of ERK1/2 (Gilmartin et al, 2011;Yamaguchi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Extracellular Signal–Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury

Collier

Schnellmann

2017

J Pharmacol Exp Ther

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The upregulation of kidney injury molecule-1 (KIM-1) has been extensively studied in various renal diseases and following acute injury; however, the initial mechanisms controlling KIM-1 expression remain limited. In this study, KIM-1 expression was examined in mouse renal cell cultures and in two different models of acute kidney injury (AKI), ischemia reperfusion (IR)-induced and lipopolysaccharide (LPS)-induced sepsis. KIM-1 mRNA increased in both AKI models, and pharmacological inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling attenuated injury-induced KIM-1 expression in the renal cortex. Toll-like receptor 4 knockout (TLR4KO) mice exhibited reduced ERK1/2 phosphorylation and attenuated KIM-1 mRNA after LPS exposure. TLR4KO mice were not protected from IR-induced ERK1/2 phosphorylation and upregulation of KIM-1 mRNA. Following renal IR injury, phosphorylation of signal transducer and activator of transcription 3 (STAT3) at serine 727 and tyrosine 705 increased downstream from ERK1/2 activation. Because phosphorylated STAT3 is a transcriptional upregulator of KIM-1 and inhibition of ERK1/2 attenuated increases in STAT3 phosphorylation, we suggest an ERK1/2-STAT3-KIM-1 pathway following renal injury. Finally, ERK1/2 inhibition in naive mice decreased KIM-1 mRNA and nuclear STAT3 phosphorylation in the cortex, indicating homeostatic regulation of KIM-1. These findings reveal renal ERK1/2 as an important initial regulator of KIM-1 expression in IR and septic AKI and at a physiologic level.Proposed mechanism of IR, LPS, and ROS-induced renal damage that initiates ERK1/2 and STAT3 phosphorylation. STAT3 then binds to the KIM-1 promoter and increases KIM-1 mRNA. By preventing ERK1/2 phosphorylation following renal injury, STAT3 phosphorylation is decreased, leading to less phosphorylated STAT3 within the nucleus, and subsequently less KIM-1 mRNA increases post injury.

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Section: Earlysupporting

confidence: 84%

Section: Discussionmentioning

confidence: 61%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Extracellular Signal–Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury

Collier

Schnellmann

2017

J Pharmacol Exp Ther

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“…17 It is probable that some of the beneficial effects of ERK1/2 inhibition are due to effects on tubular cells. Indeed, trametinib has been shown to reduce tubular damage during ischemia/reperfusion injury 49,50 and sepsis. 50 Whether ERK1/2 pathway inhibition ameliorated tubular injury upon UUO in addition to suppressing myofibroblast expansion merits further investigation.…”

Section: Discussionmentioning

confidence: 99%

The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Andrikopoulos

Kieswich

Pacheco

et al. 2018

JASN

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Background During kidney fibrosis, a hallmark and promoter of CKD (regardless of the underlying renal disorder leading to CKD), the extracellular-regulated kinase 1/2 (ERK1/2) pathway, is activated and has been implicated in the detrimental differentiation and expansion of kidney fibroblasts. An ERK1/2 pathway inhibitor, trametinib, is currently used in the treatment of melanoma, but its efficacy in the setting of CKD and renal fibrosis has not been explored.Methods We investigated whether trametinib has antifibrotic effects in two mouse models of renal fibrosis -mice subjected to unilateral ureteral obstruction (UUO) or fed an adenine-rich diet-as well as in cultured primary human fibroblasts. We also used immunoblot analysis, immunohistochemical staining, and other tools to study underlying molecular mechanisms for antifibrotic effects.Results Trametinib significantly attenuated collagen deposition and myofibroblast differentiation and expansion in UUO and adenine-fed mice. We also discovered that in injured kidneys, inhibition of the ERK1/2 pathway by trametinib ameliorated mammalian target of rapamycin complex 1 (mTORC1) activation, another key profibrotic signaling pathway. Trametinib also inhibited the ERK1/2 pathway in cultured primary human renal fibroblasts stimulated by application of TGF-b1, the major profibrotic cytokine, thereby suppressing downstream mTORC1 pathway activation. Additionally, trametinib reduced the expression of myofibroblast marker a-smooth muscle actin and the proliferation of renal fibroblasts, corroborating our in vivo data. Crucially, trametinib also significantly ameliorated renal fibrosis progression when administered to animals subsequent to myofibroblast activation.Conclusions Further study of trametinib as a potential candidate for the treatment of chronic renal fibrotic diseases of diverse etiologies is warranted.

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Pharmacological Activation of Mitochondrial Biogenesis for the Treatment of Various Pathologies

Gibbs

Scholpa

Beeson

et al. 2018

Mitochondrial Dysfunction Caused by Drugs and Environmental Toxicants

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Rapid Renal Regulation of Peroxisome Proliferator-activated Receptor γ Coactivator-1α by Extracellular Signal-Regulated Kinase 1/2 in Physiological and Pathological Conditions

Cited by 28 publications

References 43 publications

Extracellular Signal–Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury

Extracellular Signal–Regulated Kinase 1/2 Regulates Mouse Kidney Injury Molecule-1 Expression Physiologically and Following Ischemic and Septic Renal Injury

The MEK Inhibitor Trametinib Ameliorates Kidney Fibrosis by Suppressing ERK1/2 and mTORC1 Signaling

Pharmacological Activation of Mitochondrial Biogenesis for the Treatment of Various Pathologies

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