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Inhibition of fibroblast growth factor-inducible 14 attenuates experimental tubulointerstitial fibrosis and profibrotic factor expression of proximal tubular epithelial cells

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Abstract

Background and aim

As a proinflammatory cytokine, tumor necrosis factor-like weak inducer of apoptosis (TWEAK) participates in the progression of renal fibrosis by binding to its receptor, fibroblast growth factor-inducible 14 (Fn14). However, the effect of Fn14 inhibition on tubular epithelial cell-mediated tubulointerstitial fibrosis remains unclear. This study aimed to elucidate the role of TWEAK/Fn14 interaction in the development of experimental tubulointerstitial fibrosis as well as the protective effect of Fn14 knockdown on proximal tubular epithelial cells.

Methods

A murine model of unilateral ureteral obstruction was constructed in both wild-type and Fn14-deficient BALB/c mice, followed by observation of the tubulointerstitial pathologies.

Results

Fn14 deficiency ameliorated the pathological changes, including inflammatory cell infiltration and cell proliferation, accompanied by reduced production of profibrotic factors and extracellular matrix deposition. In vitro experiments showed that TWEAK dose-dependently enhanced the expression of collagen I, fibronectin, and α-smooth muscle actin in proximal tubular epithelial cells. Interestingly, TWEAK also upregulated the expression levels of Notch1/Jagged1. Fn14 knockdown and Notch1/Jagged1 inhibition also mitigated the effect of TWEAK on these cells.

Conclusions

In conclusion, TWEAK/Fn14 signals contributed to tubulointerstitial fibrosis by acting on proximal tubular epithelial cells. Fn14 inhibition might be a therapeutic strategy for protecting against renal interstitial fibrosis.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This study was supported by the National Natural Science Foundation of China (Project No.81874241) and the Innovation Capability Support Plan of Shaanxi Province (No.2019TD-034).

Author information

Author notes

  1. Mai Luo and Mengmeng Liu have contributed equally to this work.

Authors and Affiliations

  1. Core Research Laboratory, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, China

    Mai Luo, Mengmeng Liu, Kunyi Wu & Ke Li

  2. Department of Dermatology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710004, China

    Mai Luo, Wei Liu, Xiao Cui, Siyue Zhai, Hanjiang Gu, Huixia Wang & Yumin Xia

  3. College of Military Basic Education, Engineering University of PAP, Xi’an, China

    Wen Zhang

Authors
  1. Mai Luo
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  10. Ke Li
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Contributions

Mai Luo and Mengmeng Liu participated in the design of the study, and performed most experimental work. WL, XC, SZ, HG, HW, and KW carried out some experiments. WZ discussed the experimental data and contributed to the interpretation of results. KL and YX conceived and designed the study and prepared the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Ke Li or Yumin Xia.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

This study was carried out in accordance with the recommendations of the guidelines of the University Research Ethics Committee. These protocols were approved by the University Research Ethics Committee.

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Responsible Editor: John Di Battista.

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Supplementary Information

Below is the link to the electronic supplementary material.

11_2021_1455_MOESM1_ESM.tif

Supplementary file1 Fig. S1 Efficiency of siRNA transfection in HK2 cells. HK2 cells were cultured in vitro and transfected with Fn14 or control siRNA. a Efficiency of siRNA transfection assessed by confocal microscopy. b The Fn14 mRNA expression levels were assessed via qRT-PCR. c and d Western blot analysis revealed the Fn14 protein expression levels in the cell lysates. Data were obtained from three independent experiments. Representative images are shown. **P < 0.01. ns, Not significant (TIF 693 KB)

11_2021_1455_MOESM2_ESM.tif

Supplementary file2 Fig. S2 Appearance and histology changes after unilateral ureteral obstruction (UUO). a The obstructed kidney (left) and nonobstructed kidney (right) were isolated after UUO (7days). b H&E staining showing histological changes on day 7; arrows indicate injured tubules and inflammatory cell infiltration (TIF 2343 KB)

11_2021_1455_MOESM3_ESM.tif

Supplementary file3 Fig. S3 TWEAK increased proinflammatory factor production in HK2 cells. HK2 cells were cultured in vitro and stimulated with recombinant TWEAK (0–250 ng/mL) for 24 h. mRNA expression levels of IL-6 (a), TNF-α (b), and MCP-1 (c) were assessed in cells via qRT-PCR. Data were obtained from three independent experiments. *P < 0.05, **P < 0.01, compared with the blank group (TIF 870 KB)

11_2021_1455_MOESM4_ESM.tif

Supplementary file4 Fig. S4 The efficiency of Fn14 deficiency in BALB/c mice determined by Western blot analysis (TIF 335 KB)

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Luo, M., Liu, M., Liu, W. et al. Inhibition of fibroblast growth factor-inducible 14 attenuates experimental tubulointerstitial fibrosis and profibrotic factor expression of proximal tubular epithelial cells. Inflamm. Res. 70, 553–568 (2021). https://doi.org/10.1007/s00011-021-01455-0

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  • DOI: https://doi.org/10.1007/s00011-021-01455-0

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