A Novel Inhibitor of Homodimerization Targeting MyD88 Ameliorates Renal Interstitial Fibrosis by Counteracting TGF-β1-Induced EMT in Vivo and in Vitro
Open accessAbstract
Background/Aims: The TLR/MyD88/NF-κB signaling pathway has been successfully used to treat renal interstitial fibrosis (RIF). However, the exact therapeutic mechanism is still unknown. Here, we assessed the therapeutic efficacy of TJ-M2010-2, a small molecular compound that inhibits MyD88 homodimerization, in RIF induced by ischemia reperfusion injury (IRI). Methods: In vivo, RIF was induced in mice by IRI, and the mice were prophylactically treated with TJ-M2010-2. In vitro, HK-2 cells were incubated with TGF-β1 to induce EMT, and the cells were pretreated with TJ-M2010-2. Results: We found that, compared with the IRI group, the TJ-M2010-2 group showed marked attenuation of RIF and renal function injury; decreased expression of TGF-β1, α-SMA, vimentin, MMP2 and MMP9; and increased E-cadherin expression. Furthermore, TGF-β1-induced EMT was blocked by TJ-M2010-2 in HK-2 cells, as evidenced by blocked morphologic transformation, restored E-cadherin expression and inhibited α-SMA expression. In addition, compared to the TGF-β1 group, the TJ-M2010-2 group showed profound inhibition of the expression of TRAF6, p65 and Snail and upregulation of the expression of IκBα. Conclusion: This MyD88 inhibitor may be a potential therapeutic agent to ameliorate RIF.
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Combining molecular imaging of fibrosis with single-cell genomics could improve patient diagnostics, staging, prognostication, stratification, and cohort enrichment, optimizing clinical trial design.
“combining molecular imaging of fibrosis185 with cutting edge omic approaches such as single cell genomics174–176 could markedly improve patient diagnostics, staging, prognostication, stratification and cohort enrichment, which would in turn optimize clinical trial design”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [176]
Single-cell genomics methodologies have already yielded multiple new discoveries in fibrotic disease.
“Single-cell genomics methodologies have already yielded multiple new discoveries in fibrotic disease that would previously have been unattainable.”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [176]
Emerging technologies can measure multiple omic readouts (genomes, epigenomes, transcriptomes, proteomes) in single cells.
“emerging technologies are now able to measure multiple “omic” readouts (genomes, epigenomes, transcriptomes and proteomes) in single cells174–176”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [176]
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Fibrosis: from mechanisms to medicines
Henderson, N. C., Rieder, F., & Wynn, T. A. (2020) · Nature · doi:10.1038/s41586-020-2938-9 · Cited by 1,868 · see citing works
- Authors
- Liu, J.-H., He, L., Zou, Z.-M., Ding, Z.-C., Zhang, X., Wang, H., Zhou, P., Xie, L., Xing, S., & Yi, C.-Z.
- Affiliations
- Wuhan Puai Hospital (CN)
- Renmin Hospital of Wuhan University (CN)
- Tongji Hospital (CN)
- Venue
- Kidney and Blood Pressure Research
- Publisher
- S. Karger AG
- Published
- 2018
- Volume
- 43
- Issue
- 5
- Pages
- 1677-1687
- ISSN
- 1420-4096 (ISSN-L)
- 1423-0143
- OpenAlex
- W2898834801
- Cited by
- 32
- References
- 27
- Citations by year
- 2025: 5 · 2024: 5 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 10 · 2019: 3
- FWCI
- 3.51
- Type
- journal article
- Language
- en
- Update notices
- erratum (2018-10-31)
- Open access
- gold
- doi.org
- Licence
- Locations
- Kidney & Blood Pressure Research (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- tubulointerstitial fibrosis, epithelial-mesenchymal transition, TGF-β1, ischemia-reperfusion injury, HK-2 cells, TRAF6, snails, IκBα, E-cadherin, alpha-smooth muscle actin, MMP-2, MMP-9
- MeSH terms
- Actins, Animals, Cell Line, Fibrosis, Humans, Kidney, Piperazines, Thiazoles, Reperfusion Injury, Cadherins, Mice, Myeloid Differentiation Factor 88, Transforming Growth Factor beta1, Protein Multimerization, Epithelial-Mesenchymal Transition
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