Modulation of heat shock protein 90 affects TGF-β-induced collagen synthesis in human dermal fibroblast cells

Lee, Sae Bin; Lim, Aram; Rah, Dong Kyun; Kim, Kyung Soo; Min, Hyun Jin

doi:10.1016/j.tice.2016.09.002

Cited by 11 publications

(7 citation statements)

References 23 publications

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“…These molecules are well known as modulators of cell fates, but any role in controlling response to thermal stress has not before been noted in sponges. It is possible that these molecules are acting downstream of HSP70 (as noted by Yao et al (2009) and Lee et al (2016)) or as part of the control of molecular response to physical damage caused by high temperatures (Camus et al, 2005). However, the phylogenetic distance between the organisms where this has been studied and sponges is vast, and more targeted analysis is necessary to discern the true roles of these crucial molecules in this Phylum.…”

Section: Resultsmentioning

confidence: 99%

Warm temperatures, cool sponges: the effect of increased temperatures on the Antarctic spongeIsodictyasp.

González-Aravena

Kenny

Osorio

et al. 2019

PeerJ

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Although the cellular and molecular responses to exposure to relatively high temperatures (acute thermal stress or heat shock) have been studied previously, only sparse empirical evidence of how it affects cold-water species is available. As climate change becomes more pronounced in areas such as the Western Antarctic Peninsula, both long-term and occasional acute temperature rises will impact species found there, and it has become crucial to understand the capacity of these species to respond to such thermal stress. Here, we use the Antarctic sponge Isodictya sp. to investigate how sessile organisms (particularly Porifera) can adjust to acute short-term heat stress, by exposing this species to 3 and 5 °C for 4 h, corresponding to predicted temperatures under high-end 2080 IPCC-SRES scenarios. Assembling a de novo reference transcriptome (90,188 contigs, >93.7% metazoan BUSCO genes) we have begun to discern the molecular response employed by Isodictya to adjust to heat exposure. Our initial analyses suggest that TGF-β, ubiquitin and hedgehog cascades are involved, alongside other genes. However, the degree and type of response changed little from 3 to 5 °C in the time frame examined, suggesting that even moderate rises in temperature could cause stress at the limits of this organism’s capacity. Given the importance of sponges to Antarctic ecosystems, our findings are vital for discerning the consequences of short-term increases in Antarctic ocean temperature on these and other species.

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Section: Resultsmentioning

confidence: 99%

Warm temperatures, cool sponges: the effect of increased temperatures on the Antarctic spongeIsodictyasp.

González-Aravena

Kenny

Osorio

et al. 2019

PeerJ

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“…HSP90 is one of several stress proteins, and as such, its modulation is a potential therapeutic target under stressful conditions. Previous studies demonstrated that modulation of HSP90 affects TGF- β -induced collagen synthesis in dermal fibroblasts, [15], attenuates renal fibrosis through degradation of the TGF- β type II receptor in TGF- β 1-treated renal tubular cells and in a murine CKD model [44], regulates the fibroblast activation in pulmonary and hepatic fibrosis [16, 45], and hampers the inflammatory response in atherosclerosis [46] and in ischemia-reperfusion injury in the kidney [47].…”

Section: Discussionmentioning

confidence: 99%

“…Heat shock proteins (HSPs) are a family of molecular chaperone proteins; among them, HSP90 is one of the most abundant and is involved in protein folding and stabilization [13]. Various stressful conditions induce the activation of HSP90, which has been found to be upregulated during the ischemia-reperfusion injury in the kidney [14] and in models of dermal [15] and pulmonary fibrosis [16]. IS is a ligand of the aryl hydrocarbon receptor (AhR); upon binding, IS and AhR form a complex with HSP90, which translocates to the nucleus and promotes proinflammatory and fibrotic target gene transcription.…”

Section: Introductionmentioning

confidence: 99%

Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway

Milanesi

Garibaldi

Saio

et al. 2019

Oxidative Medicine and Cellular Longevity

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Indoxyl sulfate (IS) accumulation occurs early during chronic kidney disease (CKD) progression and contributes to renal dysfunction by inducing fibrosis, inflammation, oxidative stress, and tissue remodeling. Renal toxicity of high IS concentrations (250 μM) has been widely explored, particularly in resident tubular and glomerular cells, while the effect of a moderate IS increase on kidneys is still mostly unknown. To define the effects of IS accumulation on renal fibroblasts, we first analyzed kidneys of C57BL/6 mice receiving IS (0.1%) in drinking water for 12 weeks. As a next step, we treated renal fibroblasts (NRK-49F) with IS (20 μM) with or without the HSP90 inhibitor 17-AAG (1 μM). In mouse kidneys, IS increased the collagen deposition and HSP90 and α-SMA expression (immunohistochemistry) in interstitial fibroblasts and caused tubular necrosis (histological H&E and picrosirius red staining). In NRK-49F cells, IS induced MCP1, TGF-β, collagen I, α-SMA, and HSP90 gene/protein expression and Smad2/3 pathway activation. IS had no effects on fibroblast proliferation and ROS production. 17-AAG counteracted IS-induced MCP1, TGF-β, collagen I, and α-SMA expression and Smad2/3 phosphorylation. Our study demonstrates that the IS increase promotes renal fibroblast activation by a HSP90-dependent pathway and indicates HSP90 inhibition as a potential strategy to restrain IS-induced kidney inflammation and fibrosis in CKD.

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“…The systemic administration of Ang II induces cardiac fibroblasts activation including the production and release of the pro-fibrotic cytokine TGFβ [40,41]. TGFβ expression is induced by angiotensin II in kidney, vascular smooth muscle cells, and in cardiac fibroblasts [35]. We utilized the Ang II fibrotic mouse model since angiotensin II receptor blockade were mainly attributed to a reduction in extracellular protein accumulation, most likely mediated through inhibition of TGFβ and its downstream signals [42].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein

Cáceres

Chavez

Maestro

et al. 2018

Journal of Molecular and Cellular Cardiology

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Myocardial fibroblast activation coupled with extracellular matrix production is a pathological signature of myocardial fibrosis and is governed mainly by transforming growth factor TGFβ-Smad2/3 signaling. Targeting the ubiquitous TGFβ leads to cellular homeostasis deregulation with adverse consequences. We previously showed the anti-fibrotic effects upon downregulation of 90-kDa heat shock protein (Hsp90), a chaperone that associates to the TGFβ signaling cascade. In the present study, we use a fluorescent-labeled Hsp90 protein inhibitor (CTPR390-488) with specific Hsp90 binding properties to reduce myocardial pro-fibrotic events in vitro and in vivo. The mechanism of action involves the disruption of TGFβRI-Hsp90 complex, resulting in a decrease in TGFβ signaling and reduction in extracellular matrix collagen. In vivo, decreased myocardial collagen deposition was observed upon CTPR390-488 treatment in a pro-fibrotic mouse model. This is the first study demonstrating the ability of an engineered Hsp90 protein inhibitor to block collagen expression, reduce the motility of myocardial TGFβ-activated fibroblasts and ameliorate angiotensin-II induced cardiac myocardial fibrosis in vivo.

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Modulation of heat shock protein 90 affects TGF-β-induced collagen synthesis in human dermal fibroblast cells

Cited by 11 publications

References 23 publications

Warm temperatures, cool sponges: the effect of increased temperatures on the Antarctic spongeIsodictyasp.

Warm temperatures, cool sponges: the effect of increased temperatures on the Antarctic spongeIsodictyasp.

Indoxyl Sulfate Induces Renal Fibroblast Activation through a Targetable Heat Shock Protein 90-Dependent Pathway

Reduction of cardiac TGFβ-mediated profibrotic events by inhibition of Hsp90 with engineered protein

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