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Endoplasmic reticulum protein TXNDC5 promotes renal fibrosis by enforcing TGF-β signaling in kidney fibroblasts
Yen-Ting Chen, … , Shuei-Liong Lin, Kai-Chien Yang
Yen-Ting Chen, … , Shuei-Liong Lin, Kai-Chien Yang
Published January 19, 2021
Citation Information: J Clin Invest. 2021;131(5):e143645. https://doi.org/10.1172/JCI143645.
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Research Article Cell biology Nephrology Article has an altmetric score of 10

Endoplasmic reticulum protein TXNDC5 promotes renal fibrosis by enforcing TGF-β signaling in kidney fibroblasts

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Abstract

Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney disease (CKD), often results in diffuse kidney scarring and predisposes to end-stage renal disease. Currently, there is no effective therapy against renal fibrosis. Recently, our laboratory identified an ER-resident protein, thioredoxin domain containing 5 (TXNDC5), as a critical mediator of cardiac fibrosis. Transcriptome analyses of renal biopsy specimens from patients with CKD revealed marked TXNDC5 upregulation in fibrotic kidneys, suggesting a potential role of TXNDC5 in renal fibrosis. Employing multiple fluorescence reporter mouse lines, we showed that TXNDC5 was specifically upregulated in collagen-secreting fibroblasts in fibrotic mouse kidneys. In addition, we showed that TXNDC5 was required for TGF-β1–induced fibrogenic responses in human kidney fibroblasts (HKFs), whereas TXNDC5 overexpression was sufficient to promote HKF activation, proliferation, and collagen production. Mechanistically, we showed that TXNDC5, transcriptionally controlled by the ATF6-dependent ER stress pathway, mediated its profibrogenic effects by enforcing TGF-β signaling activity through posttranslational stabilization and upregulation of type I TGF-β receptor in kidney fibroblasts. Using a tamoxifen-inducible, fibroblast-specific Txndc5 knockout mouse line, we demonstrated that deletion of Txndc5 in kidney fibroblasts mitigated the progression of established kidney fibrosis, suggesting the therapeutic potential of TXNDC5 targeting for renal fibrosis and CKD.

Authors

Yen-Ting Chen, Pei-Yu Jhao, Chen-Ting Hung, Yueh-Feng Wu, Sung-Jan Lin, Wen-Chih Chiang, Shuei-Liong Lin, Kai-Chien Yang

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Figure 3

Knockdown of TXNDC5 attenuated TGF-β1–induced HKF activation and ECM production; overexpression of TXNDC5 was sufficient to trigger HKF activation and ECM production.

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Knockdown of TXNDC5 attenuated TGF-β1–induced HKF activation and ECM pro...
(A) Protein and (B) transcript expression levels of fibroblast activation marker (periostin) and ECM proteins (COL1A1, fibronectin, and CCN2) were increased in control (Scramble) HKFs following TGF-β1 (10 ng/mL) treatment. Knockdown of TXNDC5 attenuated the upregulation of these fibrogenic markers induced by TGF-β1 in HKFs (n = 5–10). (C) Overexpression of TXNDC5 was sufficient to induce upregulation of fibroblast activation marker (Periostin) and ECM proteins (COL1A1, fibronectin) in HKFs (n = 3–10). (D) Treatment of TGF-β1 (10 ng/mL) increased the cellular proliferation activity of HKFs, which was abrogated by TXNDC5 knockdown. (E) Overexpression of TXNDC5 increased the cellular proliferation activity of HKFs. In D and E, n = 10. Data are representative of 3 or more independent experimental replicates. For all panels, data are presented as mean ± SEM. The statistical significance of differences for 2 groups was determined by 2-sided t test and among 3 or more groups it was determined using 1-way ANOVA, followed by Sidak’s post hoc tests. *P < 0.05, **P < 0.01, ***P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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