Hypoxia inhibits primary cilia formation and reduces cell-mediated contraction in stress-deprived rat tail tendon fascicles

Lavagnino, Michael; Oslapas, Anna N.; Gardner, Keri; Arnoczky, Steven P.

doi:10.11138/mltj/2016.6.2.193

Cited by 11 publications

(8 citation statements)

References 27 publications

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“…It remains uncertain if hypoxia can maintain and stabilize the primary cilia or it would inhibit primary cilia formation (Verghese et al, 2011 ; Ding et al, 2015 ; Lavagnino et al, 2016 ; Resnick, 2016 ). To investigate the effect of chronic hypoxia, primary cilia were labeled with the cilia marker acetylated-α-tubulin.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies demonstrate a link between cilia length and hypoxia-inducible mechanisms. In tendon cells, hypoxia inhibits primary cilia formation and cellular mechano-responsiveness (Lavagnino et al, 2016 ). However, studies in different hypoxic models using renal epithelial cells indicate that primary cilia are longer and that expression of HIF maintains primary cilia length (Verghese et al, 2011 ; Ding et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Here, we examined the effects of hypoxic high-altitude on the kidneys in adult and fetal sheep. We also took this opportunity to study cilia length-function relationship in response to chronic hypobaric hypoxia, because it has been reported that HIF could alter the structural length of primary cilia in hypoxic in vitro models (Verghese et al, 2011 ; Ding et al, 2015 ; Lavagnino et al, 2016 ; Resnick, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

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Chronic Hypobaric Hypoxia Modulates Primary Cilia Differently in Adult and Fetal Ovine Kidneys

et al. 2017

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Hypoxic environments at high altitude have significant effects on kidney injury. Following injury, renal primary cilia display length alterations. Primary cilia are mechanosensory organelles that regulate tubular architecture. The effect of hypoxia on cilia length is still controversial in cultured cells, and no corresponding in vivo study exists. Using fetal and adult sheep, we here study the effect of chronic hypobaric hypoxia on the renal injury, intracellular calcium signaling and the relationship between cilia length and cilia function. Our results show that although long-term hypoxia induces renal fibrosis in both fetal and adult kidneys, fetal kidneys are more susceptible to hypoxia-induced renal injury. Unlike hypoxic adult kidneys, hypoxic fetal kidneys are characterized by interstitial edema, tubular disparition and atrophy. We also noted that there is an increase in the cilia length as well as an increase in the cilia function in the hypoxic fetal proximal and distal collecting epithelia. Hypoxia, however, has no significant effect on primary cilia in the adult kidneys. Increased cilia length is also associated with greater flow-induced intracellular calcium signaling in renal epithelial cells from hypoxic fetuses. Our studies suggest that while hypoxia causes renal fibrosis in both adult and fetal kidneys, hypoxia-induced alteration in cilia length and function are specific to more severe renal injuries in fetal hypoxic kidneys.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chronic Hypobaric Hypoxia Modulates Primary Cilia Differently in Adult and Fetal Ovine Kidneys

et al. 2017

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“…Aspirin is a classic, representative NSAID, and so understanding its effects on TSCs can give us useful information regarding other NSAIDs. The cellular niche of tenocytes and TSCs is significant to tendinopathy; for example, Del Buono et al reported that increasing metalloproteases may induce tendinopathy [27] and Lavagnino et al showed that a hypoxic environment may lead to inability to respond to strain-based rehabilitation modalities in chronic tendinopathy [28]. TSCs are at the core of the cause, development, and healing of tendinopathy.…”

Section: Discussionmentioning

confidence: 99%

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Wang

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice to relieve fever and pain. Aspirin, as a representative NSAID, has been widely used in the treatment of tendinopathy. Some reports have demonstrated that aspirin can induce apoptosis in cancer cells. However, evidence regarding aspirin treatment for tendinopathy, especially the effect of this treatment on tendon stem cells (TSCs), is lacking. Understanding the effect of aspirin on tendinopathy may provide a basis for the rational use of NSAIDs in clinical practice. The aim of our study was to determine whether aspirin induces apoptosis in rat TSCs via the Wnt/β-catenin pathway. Methods: First, we used flow cytometry and fluorescence to detect TSC apoptosis. Protein expression of the apoptosis-related caspase-3 pathway was investigated via western blot analysis. Next, we used western blotting to determine the effect of aspirin on the Wnt/β-catenin pathway. We used immunostaining to detect the levels of Bcl2, cleaved caspase-3, and P-β-catenin in the Achilles tendon. Finally, we used flow cytometry, fluorescence, and western blotting to investigate the aspirin-induced apoptosis of TSCs via the Wnt/β-catenin pathway. Results: Aspirin induced morphological apoptosis in rat TSCs via the mitochondrial/caspase-3 pathway and induced cellular apoptosis in the Achilles tendon. Apoptosis was partly reversed after adding the Wnt signaling activator Wnt3a and lithium chloride (LiCl, a GSK-3β inhibitor). Aspirin administration led to a dose-dependent increase in COX-2 expression. Apoptosis was promoted after adding the COX-2 inhibitor NS398. Conclusion: The Wnt/β-catenin pathway plays a vital role in aspirin-induced apoptosis by regulating mitochondrial/caspase-3 function. Elevating COX-2 levels may protect cells against apoptosis. More importantly, the results remind us to consider the apoptotic effect of aspirin on TSCs and tendon cells when aspirin is administered to treat tendinopathy. The relationship between the positive and negative effects of aspirin remains a subject for future study.

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“…In many of these diseases, a prominent role is played by redox, proteostatic and other kinds of cellular stress [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ]. Consistently, primary cilia and Hh signaling can respond to redox and other stress signals, and their function may also protect cells from such stresses [ 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. In this context, recent findings connecting primary cilia and Hh signaling to NRF2 (nuclear factor erythroid 2-related factor 2) are of special relevance.…”

Section: Primary Cilia As Cellular Antennaementioning

confidence: 99%

NRF2 and Primary Cilia: An Emerging Partnership

et al. 2020

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When not dividing, many cell types target their centrosome to the plasma membrane, where it nucleates assembly of a primary cilium, an antenna-like signaling structure consisting of nine concentric microtubule pairs surrounded by membrane. Primary cilia play important pathophysiological roles in many tissues, their dysfunction being associated with cancer and ciliopathies, a diverse group of congenital human diseases. Several recent studies have unveiled functional connections between primary cilia and NRF2 (nuclear factor erythroid 2-related factor 2), the master transcription factor orchestrating cytoprotective responses to oxidative and other cellular stresses. These NRF2-cilia relationships are reciprocal: primary cilia, by promoting autophagy, downregulate NRF2 activity. In turn, NRF2 transcriptionally regulates genes involved in ciliogenesis and Hedgehog (Hh) signaling, a cilia-dependent pathway with major roles in embryogenesis, stem cell function and tumorigenesis. Nevertheless, while we found that NRF2 stimulates ciliogenesis and Hh signaling, a more recent study reported that NRF2 negatively affects these processes. Herein, we review the available evidence linking NRF2 to primary cilia, suggest possible explanations to reconcile seemingly contradictory data, and discuss what the emerging interplay between primary cilia and NRF2 may mean for human health and disease.

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Hypoxia inhibits primary cilia formation and reduces cell-mediated contraction in stress-deprived rat tail tendon fascicles

Cited by 11 publications

References 27 publications

Chronic Hypobaric Hypoxia Modulates Primary Cilia Differently in Adult and Fetal Ovine Kidneys

Chronic Hypobaric Hypoxia Modulates Primary Cilia Differently in Adult and Fetal Ovine Kidneys

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

NRF2 and Primary Cilia: An Emerging Partnership

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