scholarly journals Integrin β3 Induction Promotes Tubular Cell Senescence and Kidney Fibrosis

2021 ◽  
Vol 9 ◽  
Author(s):  
Shen Li ◽  
Song Jiang ◽  
Qingyan Zhang ◽  
Bo Jin ◽  
Daoyuan Lv ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Cell Senescence ◽  
Tubular Cell ◽  
Integrin Signaling ◽  
Kidney Fibrosis ◽  
Tubular Cells ◽  
Integrin Β3 ◽  
Pathway Activation ◽  
Biologic Process

Tubular cell senescence is a common biologic process and contributes to the progression of chronic kidney disease (CKD); however, the molecular mechanisms regulating tubular cell senescence are poorly understood. Here, we report that integrin β3 (ITGB3) expression was increased in tubular cells and positively correlated with fibrosis degree in CKD patients. ITGB3 overexpression could induce p53 pathway activation and the secretion of TGF-β, which, in turn, resulted in senescent and profibrotic phenotype change in cultured tubular cells. Moreover, according to the CMAP database, we identified isoliquiritigenin (ISL) as an agent to inhibit ITGB3. ISL treatment could suppress Itgb3 expression, attenuate cellular senescence, and prevent renal fibrosis in mice. These results reveal a crucial role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction for kidney fibrosis.

scholarly journals Wnt9a Promotes Renal Fibrosis by Accelerating Cellular Senescence in Tubular Epithelial Cells

2018 ◽  
Vol 29 (4) ◽  
pp. 1238-1256 ◽  
Author(s):  
Congwei Luo ◽  
Shan Zhou ◽  
Zhanmei Zhou ◽  
Yahong Liu ◽  
Li Yang ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Cellular Senescence ◽  
Renal Fibrosis ◽  
Ischemia Reperfusion ◽  
Ectopic Expression ◽  
Cell Senescence ◽  
Tubular Cell ◽  
Tubular Epithelial Cells ◽  
Tubular Cells ◽  
Renal Tubular Cells

Cellular senescence is associated with renal disease progression, and accelerated tubular cell senescence promotes the pathogenesis of renal fibrosis. However, the underlying mechanism is unknown. We assessed the potential role of Wnt9a in tubular cell senescence and renal fibrosis. Compared with tubular cells of normal subjects, tubular cells of humans with a variety of nephropathies and those of several mouse models of CKD expressed high levels of Wnt9a that colocalized with the senescence-related protein p16INK4A. Wnt9a expression level correlated with the extent of renal fibrosis, decline of eGFR, and expression of p16INK4A. Furthermore, ectopic expression of Wnt9a after ischemia-reperfusion injury (IRI) induced activation of β-catenin and exacerbated renal fibrosis. Overexpression of Wnt9a exacerbated tubular senescence, evidenced by increased detection of p16INK4A expression and senescence-associated β-galactosidase activity. Conversely, shRNA-mediated knockdown of Wnt9a repressed IRI-induced renal fibrosis in vivo and impeded the growth of senescent tubular epithelial cells in culture. Notably, Wnt9a-induced renal fibrosis was inhibited by shRNA-mediated silencing of p16INK4A in the IRI mouse model. In a human proximal tubular epithelial cell line and primary renal tubular cells, Wnt9a remarkably upregulated levels of senescence-related p16INK4A, p19ARF, p53, and p21 and decreased the phosphorylation of retinoblastoma protein. Wnt9a also induced senescent tubular cells to produce TGF-β1, which promoted proliferation and activation in normal rat kidney fibroblasts. Thus, Wnt9a drives tubular senescence and fibroblast activation. Furthermore, the Wnt9a–TGF-β pathway appears to create a reciprocal activation loop between senescent tubular cells and activated fibroblasts that promotes and accelerates the pathogenesis of renal fibrosis.

scholarly journals PP2Acα promotes macrophage accumulation and activation to exacerbate tubular cell death and kidney fibrosis through activating Rap1 and TNFα production

2021 ◽  
Author(s):  
Yan Liang ◽  
Xiaoli Sun ◽  
Mingjie Wang ◽  
Qingmiao Lu ◽  
Mengru Gu ◽  
...  
Keyword(s):  
Cell Death ◽  
Tubular Cell ◽  
Kidney Fibrosis ◽  
Tubular Cells ◽  
Ureter Obstruction ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Rap1 Activation ◽  
Necrosis Factor ◽  
Macrophage Accumulation

AbstractMacrophage accumulation and activation play an essential role in kidney fibrosis; however, the underlying mechanisms remain to be explored. By analyzing the kidney tissues from patients and animal models with kidney fibrosis, we found a large induction of PP2Acα in macrophages. We then generated a mouse model with inducible macrophage ablation of PP2Acα. The knockouts developed less renal fibrosis, macrophage accumulation, or tubular cell death after unilateral ureter obstruction or ischemic reperfusion injury compared to control littermates. In cultured macrophages, PP2Acα deficiency resulted in decreased cell motility by inhibiting Rap1 activity. Moreover, co-culture of PP2Acα−/− macrophages with tubular cells resulted in less tubular cell death attributed to downregulated Stat6-mediated tumor necrosis factor α (TNFα) production in macrophages. Together, this study demonstrates that PP2Acα promotes macrophage accumulation and activation, hence accelerates tubular cell death and kidney fibrosis through regulating Rap1 activation and TNFα production.

Busulfan Selectively Induces Cellular Senescence Via a p53-Independent but Erk-p38 MAPK-Dependent Mechanism.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3199-3199 ◽  
Author(s):  
Virginia Probin ◽  
Aiping Bai ◽  
Daohong Zhou ◽  
Yong Wang
Keyword(s):  
P38 Mapk ◽  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Cell Senescence ◽  
Independent Manner ◽  
Hematopoietic Stem ◽  
Human Diploid Fibroblasts ◽  
Wi38 Cell ◽  
P53 Activation ◽  
Dependent Mechanism

Abstract Busulfan (BU), an alkylating agent, has been used extensively for the depletion of leukemia cells and normal hematopoietic stem cells (HSCs) prior to bone marrow transplantation. However, its mechanism(s) of action is unknown. Our laboratory has previously shown that BU primarily depletes HSCs by induction of senescence, but not apoptosis. In the present study, we investigated the molecular mechanisms whereby BU induces cellular senescence utilizing WI38 human diploid fibroblasts as a model system. We found that WI38 fibroblasts incubated with BU (from 7.5 to 120μM) for 24 h underwent senescence but not apoptosis in a dose-independent manner, whereas cells incubated with 80μM and 20μM etoposide (Etop) committed to apoptosis and senescence, respectively. The induction of WI38 cell senescence by Etop was associated with p53 activation and could be attenuated by down-regulation of p53 using a-PFT or p53 siRNA. In contrast, WI38 cell senescence induced by BU was associated with prolonged activation of Erk, p38 and JNK, and could be suppressed by the inhibition of Erk and p38 MAPKs with PD98059 and SB203580, respectively. Upon release from Erk and p38 inhibition, BU-treated cells proceeded to DNA synthesis and cell division. However, inhibition of p53 with a-PFT or p53 siRNA, or JNK with SP600125, failed to protect WI38 cells from BU-induced senescence. These findings suggest that BU is a distinctive chemotherapeutic agent that can selectively induce cellular senescence through the Erk and p38 MAPK pathways.

scholarly journals SRT1720 Protects Against CSE-Induced Cellular Senescence via Accelerates of FOXO3-PINK1-mediated Mitophagy

2021 ◽  
Author(s):  
hui Jiang ◽  
Changyong Fu ◽  
Dong Yuan ◽  
Yaona Jiang ◽  
Yaqing Li
Keyword(s):  
Epithelial Cell ◽  
Cellular Senescence ◽  
Airway Resistance ◽  
Molecular Mechanisms ◽  
Bronchial Epithelial Cell ◽  
Protective Role ◽  
Cell Senescence ◽  
Sirtuin 1 ◽  
Bronchial Epithelial ◽  
Mitochondrial Injury

Abstract BackgroundChronic obstructive pulmonary disease (COPD) is often associate with cigarette smoke extract (CSE)-introduced bronchial epithelial cell senescence, mitochondrial fragmentation. Sirtuin-1(Sirt1) has been reported to play a crucial role in mitochondrial homeostasis and confers a protective role against the onset and development of CSE introduced bronchial epithelial cell senescence in COPD although the precise mechanism(s) remain elusive. Here we hypothesized that SRT1720, a pharmacological SIRT1720 activator, exerts protect against COPD by activating PINK1 mediated mitophagy, en route to preserved mitochondrial homeostasis.MethodsCOPD rats model was established by CS exposure. During 6 months of SRT1720 treatment, airway resistance, cellular senescence and mitochondrial injury, mitophagy in the lung tissues of model rats were examined by western blot(WB) and histochemical and immunofluorescence staining. Transmission electron microscopy was also carried to elucidate the effects of SRT1720.Human bronchial epithelial cells(HBEC) were used to clarify the underlying molecular mechanisms. ResultDuring the introduction of CSE in cellular or rats, administration of SRT1720 improved airway resistance, cellular senescence and mitochondrial injury, accompanied with suppressed autophagy and mitophagy. Mitochondrial damage, cellular senescence and lung injury under contrast exposure were more severe in FOXO3 or Pink1 deficient cells and mice than in SRT1720 groups. Activation of Sirt1 by treating with SRT1720 induces autophagy enhanced. A Decrease in sirt1 expression caused by selisistat treatment promotes senescence.ConclusionsTaken together, our data suggested that suppressed SIRT1/FOXO3/Pink1 signaling mediated mitophagy played a protective role in COPD by reducing mitochondrial reactive oxygen species (ROS).

scholarly journals Integrin-mediated adhesions in regulation of cellular senescence

2020 ◽  
Vol 6 (19) ◽  
pp. eaay3909
Author(s):  
Eun-Young Shin ◽  
Jin-Hee Park ◽  
Soon-Tae You ◽  
Chan-Soo Lee ◽  
So-Yoon Won ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Molecular Mechanisms ◽  
Human Fibroblasts ◽  
Integrin Signaling ◽  
Data Link ◽  
Interacting Protein ◽  
Amphiphysin 1 ◽  
Species Production

Bioinformatic and functional data link integrin-mediated cell adhesion to cellular senescence; however, the significance of and molecular mechanisms behind these connections are unknown. We now report that the focal adhesion–localized βPAK-interacting exchange factor (βPIX)–G protein–coupled receptor kinase interacting protein (GIT) complex controls cellular senescence in vitro and in vivo. βPIX and GIT levels decline with age. βPIX knockdown induces cellular senescence, which was prevented by reexpression. Loss of βPIX induced calpain cleavage of the endocytic adapter amphiphysin 1 to suppress clathrin-mediated endocytosis (CME); direct competition of GIT1/2 for the calpain-binding site on paxillin mediates this effect. Decreased CME and thus integrin endocytosis induced abnormal integrin signaling, with elevated reactive oxygen species production. Blocking integrin signaling inhibited senescence in human fibroblasts and mouse lungs in vivo. These results reveal a central role for integrin signaling in cellular senescence, potentially identifying a new therapeutic direction.

Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis

Life Sciences ◽  
2020 ◽  
Vol 257 ◽  
pp. 118116 ◽  
Author(s):  
Tao Liu ◽  
Qunfang Yang ◽  
Xuan Zhang ◽  
Rongxing Qin ◽  
Wenjun Shan ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Tubular Epithelial Cell ◽  
Cell Senescence ◽  
Renal Tubular Epithelial Cell ◽  
Kidney Fibrosis ◽  
Renal Tubular

scholarly journals Hyperhomocysteinemia exacerbates ischemia-reperfusion injury-induced acute kidney injury by mediating oxidative stress, DNA damage, JNK pathway, and apoptosis

2021 ◽  
Vol 16 (1) ◽  
pp. 537-543
Author(s):  
Mei Zhang ◽  
Jing Yuan ◽  
Rong Dong ◽  
Jingjing Da ◽  
Qian Li ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Cell Apoptosis ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Tubular Cell ◽  
Tubular Injury ◽  
Jnk Pathway ◽  
Pathway Activation

Abstract Background Hyperhomocysteinemia (HHcy) plays an important role in the progression of many kidney diseases; however, the relationship between HHcy and ischemia-reperfusion injury (IRI)-induced acute kidney injury (IRI-induced AKI) is far from clear. In this study, we try to investigate the effect and possible mechanisms of HHcy on IRI-induced AKI. Methods Twenty C57/BL6 mice were reared with a regular diet or high methionine diet for 2 weeks (to generate HHcy mice); after that, mice were subgrouped to receive sham operation or ischemia-reperfusion surgery. Twenty four hour after reperfusion, serum creatinine, blood urea nitrogen, and Malondialdehyde (MDA) were measured. H&E staining for tubular injury, western blot for γH2AX, JNK, p-JNK, and cleaved caspase 3, and TUNEL assay for tubular cell apoptosis were also performed. Results Our results showed that HHcy did not influence the renal function and histological structure, as well as the levels of MDA, γH2AX, JNK, p-JNK, and tubular cell apoptosis in control mice. However, in IRI-induced AKI mice, HHcy caused severer renal dysfunction and tubular injury, higher levels of oxidative stress, DNA damage, JNK pathway activation, and tubular cell apoptosis. Conclusion Our results demonstrated that HHcy could exacerbate IRI-induced AKI, which may be achieved through promoting oxidative stress, DNA damage, JNK pathway activation, and consequent apoptosis.

scholarly journals Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

2021 ◽  
Vol 22 (6) ◽  
pp. 2881
Author(s):  
Clara Lefranc ◽  
Malou Friederich-Persson ◽  
Fabienne Foufelle ◽  
Aurélie Nguyen Dinh Cat ◽  
Frédéric Jaisser
Keyword(s):  
Quality Control ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Oxidative Stress ◽  
Specific Effects

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

scholarly journals The Jekyll and Hyde of Cellular Senescence in Cancer

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 208
Author(s):  
Dilara Demirci ◽  
Bengisu Dayanc ◽  
Fatma Aybuke Mazi ◽  
Serif Senturk
Keyword(s):  
Cancer Cell ◽  
Cellular Senescence ◽  
Expression Profiles ◽  
Treatment Strategies ◽  
Gene Expression Profiles ◽  
Therapy Resistance ◽  
Disease Recurrence ◽  
Adverse Outcomes ◽  
Cell Senescence ◽  
Great Promise

Cellular senescence is a state of stable cell cycle arrest that can be triggered in response to various insults and is characterized by distinct morphological hallmarks, gene expression profiles, and the senescence-associated secretory phenotype (SASP). Importantly, cellular senescence is a key component of normal physiology with tumor suppressive functions. In the last few decades, novel cancer treatment strategies exploiting pro-senescence therapies have attracted considerable interest. Recent insight, however, suggests that therapy-induced senescence (TIS) elicits cell-autonomous and non-cell-autonomous implications that potentially entail detrimental consequences, reflecting the Jekyll and Hyde nature of cancer cell senescence. In essence, the undesirable manifestations that generally culminate in inflammation, cancer stemness, senescence reversal, therapy resistance, and disease recurrence are dictated by the persistent accumulation of senescent cells and the SASP. Thus, mitigating these pro-tumorigenic effects by eliminating these cells or inhibiting their SASP production holds great promise for developing innovative therapeutic strategies. In this review, we describe the fundamental aspects and dynamics of cancer cell senescence and summarize the comprehensive research on the adverse outcomes of TIS. Furthermore, we underline the rationale and motivation of emerging senotherapeutic modalities surrounding the removal of senescent cells and the SASP to help maximize the overall efficacy of cancer therapies.

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