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

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 11

Induced deletion of Txndc5 in renal fibroblasts mitigated the progression of established kidney fibrosis.

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Induced deletion of Txndc5 in renal fibroblasts mitigated the progressio...
(A) Illustration of experimental design to induce Txndc5 deletion specifically in renal fibroblasts in mouse kidneys with established fibrosis. (B) Picrosirius red staining of kidney sections from Col1a2-Cre and Txndc5cKO mice. Ten days after UUO, Col1a2-Cre and Txndc5cKO mice showed a similar extent of renal fibrosis prior to tamoxifen injection. Eleven days after tamoxifen treatment, the fibrotic areas more than doubled (increased from 5.1% to 10.6%) in Col1a2-Cre, but barely changed in Txndc5cKO (changed from 5.3% to 6.9%) mouse kidneys (n = 5–6). Scale bar: 50 μm. (C) Protein expression levels of fibroblast activation marker (periostin), ECM (CCN2), and TGFBR1 in whole-kidney lysate from Col1a2-Cre and Txndc5cKO mice (n = 4–6). (D) Schematic summary of the proposed profibrotic mechanisms by which TXNDC5 contributes to the pathogenesis of renal fibrosis. TF: transcription factor. Data are representative of 3 or more independent experimental replicates. For all panels, data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 by 2-sided t test.