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ResearchIn-Press PreviewCell biologyNephrology Free access | 10.1172/JCI143645

Endoplasmic reticulum protein TXNDC5 promotes renal fibrosis by enforcing TGFβ signaling in kidney fibroblasts

Yen-Ting Chen,1 Pei-Yu Jhao,1 Chen-Ting Hung,1 Yueh-Feng Wu,2 Sung-Jan Lin,3 Wen-Chih Chiang,4 Shuei-Liong Lin,5 and Kai-Chien Yang1

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Chen, Y. in: JCI | PubMed | Google Scholar

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Jhao, P. in: JCI | PubMed | Google Scholar

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Hung, C. in: JCI | PubMed | Google Scholar

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Wu, Y. in: JCI | PubMed | Google Scholar

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Lin, S. in: JCI | PubMed | Google Scholar |

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Chiang, W. in: JCI | PubMed | Google Scholar |

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Lin, S. in: JCI | PubMed | Google Scholar |

1Department and Graduate Institute of Pharmacology, National Taiwan University College of Medicine, Taipei City, Taiwan

2Department of Biomedical Engineering, National Taiwan University College of Medicine and College of Engineering, Taipei City, Taiwan

3Department of Dermatology, National Taiwan University Hospital and College of Medicine, Taipei City, Taiwan

4Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei City, Taiwan

5Department and Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei City, Taiwan

Find articles by Yang, K. in: JCI | PubMed | Google Scholar |

Published January 19, 2021 - More info

J Clin Invest. https://doi.org/10.1172/JCI143645.
Copyright © 2021, American Society for Clinical Investigation
Published January 19, 2021 - Version history
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Abstract

Renal fibrosis, a common pathological manifestation of virtually all types of chronic kidney diseases (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 CKD patients revealed marked TXNDC5 upregulation in fibrotic kidneys, suggesting a potential role of TXNDC5 in renal fibrosis. Employing multiple fluorescent 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 TGFβ1-induced fibrogenic responses in human kidney fibroblasts (HKF), whereas TXNDC5 over-expression was sufficient to promote HKF activation, proliferation and collagen production. Mechanistically, we showed that TXNDC5, transcriptionally controlled by ATF6-dependent ER stress pathway, mediates its pro-fibrogenic effects by enforcing TGFβ signaling activity through post-translational stabilization and upregulation of type I TGFβ 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. 

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