Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury

Susnik, Nathan; Sörensen-Zender, Inga; Rong, Song; Vietinghoff, Sibylle von; Xia, Lu; Rubera, Isabelle; Tauc, Michel; Falk, Christine S.; Alexander, Warren S.; Melk, Anette; Haller, H.; Schmitt, Roland

doi:10.1038/ki.2013.525

Cited by 35 publications

(26 citation statements)

References 41 publications

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“…Accumulating experimental evidence indicates that macrophage phenotypes may drive kidney injury and fibrosis [17]. We examined changes in macrophage phenotypes further.…”

Section: Resultsmentioning

confidence: 99%

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Tian¹,

Shao²,

Xie³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Kidney injury molecule-1 (KIM-1) is highly expressed in renal tubular cells after injury and is usually regarded as an early biomarker of acute kidney injury(AKI). The aim of this study was to determine the role of KIM-1 in the development of renal tubular injury Methods: Clinical samples, three different animal models and in vitro experiments were utilized to determine the possible mechanism underlying the involvement of KIM-1 in kidney injury. Results: Both plasma and urinary KIM-1 expression levels were significantly higher in AKI and chronic kidney disease (CKD) patients than in healthy volunteers, and urinary KIM-1 expression was significantly higher in CKD patients than in AKI patients. According to the results of our research involving three different mouse models, KIM-1 expression was significantly increased during the early stage of kidney injury and was persistently elevated in renal fibrosis. Our immunofluorescence staining results indicated that KIM-1-positive tubules were surrounded by macrophage infiltrates in regions of kidney injury. Moreover, our transwell, western blotting and real-time PCR data showed that macrophage migration and phenotype transitions were mediated by KIM-1 through the mitogen-activated protein kinase (MAPK) pathway. MAPK pathway inhibition could significantly reverse the effects of KIM-1 with respect to these macrophage phenotype changes and migration. Conclusions: KIM-1 expression was markedly elevated in both acute and chronic kidney injury and may play a pivotal role in macrophage activation via the MAPK pathway in kidney disease.

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“…Accumulating experimental evidence indicates that macrophage phenotypes may drive kidney injury and fibrosis [17]. We examined changes in macrophage phenotypes further.…”

Section: Resultsmentioning

confidence: 99%

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Tian¹,

Shao²,

Xie³

et al. 2017

Cell Physiol Biochem

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“…2), we wanted to determine if loss of Sav1 affects the response to injury by AAN. We administered AA to Ctrl and KS mice at a dose of 5 mg/kg of body weight, which was previously shown to result in mild to negligible AKI in normal healthy mice (51). Intraperitoneal introduction of AA into KS mice 3 weeks after ablation of Sav1 expression resulted in dramatic increases in the expression levels of all profibrotic genes (Col1a1, Col3a1, Col4a1, Fn, Tgf␤1, and Vimentin) examined compared to those in AA-treated Ctrl mice with no Sav1 loss ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Leung

Wilson

Voltzke

et al. 2017

Molecular and Cellular Biology

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Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.

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“…These proteins may serve a special and pleiotropic biological function on immune regulation, hematopoietic stem cells, cancer, nervous system and embryonic development (25). Previous studies have shown that the JAK/STAT signal transduction pathways are involved in the development of the central nervous system and nerve cell proliferation, survival, differentiation, and they are closely associated with brain tumors, central nervous system diseases, including cerebral ischemia, and pathological physiological processes (26). The present study found that ursolic acid treatment reduced the increase of the protein expression levels of p-STAT3 in I/R-IAKI rats.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective effects of ursolic acid on ischemia/reperfusion-induced acute kidney injury through oxidative stress, inflammation and the inhibition of STAT3 and NF-κB activities

Peng

Ren

Lan

et al. 2016

Molecular Medicine Reports

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Abstract. Ursolic acid, a pentacyclic triterpene compound with low toxicity and easy availability, has a variety of biological activities, including antitumor, antioxidant, antihepatitis, anti-inflammatory and antibacterial effects. The present study aimed to investigate the renoprotective effects of ursolic acid on ischemia/reperfusion-induced acute kidney injury (I/R-IAKI) in rats associated with its antioxidant and anti-inflammatory effects, as well as interference with the signal transducer and activator of transcription (STAT)3/nuclear factor (NF)-κB signaling pathway. The present study demonstrated that pre-treatment with ursolic acid significantly increased renal functioning and attenuated increases of serum angiotensin II levels in rats subjected to I/R-IAKI. In addition, I/R-IAKI-induced inflammation and oxidative stress were significantly reduced by pre-treatment with ursolic acid. Furthermore, ursolic acid significantly suppressed the upregulation of STAT3, NF-κB and caspase-3 activities in rats following I/R-IAKI. These results indicated that ursolic acid may be a potential drug for reducing I/R-IAKI through suppression of inflammation and oxidative stress damage, as well as modulation of STAT3 and NF-κB activities.

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Ablation of proximal tubular suppressor of cytokine signaling 3 enhances tubular cell cycling and modifies macrophage phenotype during acute kidney injury

Cited by 35 publications

References 41 publications

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Kidney Injury Molecule-1 is Elevated in Nephropathy and Mediates Macrophage Activation via the Mapk Signalling Pathway

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis

Renoprotective effects of ursolic acid on ischemia/reperfusion-induced acute kidney injury through oxidative stress, inflammation and the inhibition of STAT3 and NF-κB activities

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