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Kidney Week

Abstract: TH-PO468

Regulation of Renal Fibroblast Functions by Myocardin-Related Transcription Factor Focal Adhesion in Response to TGFβ1

Session Information

  • CKD: Mechanisms - I
    November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Sakai, Norihiko, Division of Blood Purification, Kanazawa University Hospital, Kanazawa, Japan
  • Sato, Koichi, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Ogura, Hisayuki, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Miyagawa, Taro, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Kitajima, Shinji, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Toyama, Tadashi, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Hara, Akinori, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Iwata, Yasunori, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Shimizu, Miho, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
  • Furuichi, Kengo, Department of Nephrology, Kanazawa Medical University, Kahoku-Gun, Japan
  • Wada, Takashi, Department of Nephrology and Laboratory Medicine, Kanazawa University, Kanazawa, Japan
Background

Renal fibrosis is a common pathway resulting in end-stage renal disease regardless of their etiologies. As pathological findings, tissue fibrosis is characterized by the accumulation of fibroblasts and the excessive deposition of extracellular matrix (ECM). In general, cells can contact with ECM via multiprotein structures called focal adhesion composed of various cytoskeletal proteins and integrins. We have previously found the lipid mediator lysophosphatidic acid (LPA) and one of its receptors, LPA1, contributes to the development of renal fibrosis through connective tissue growth factor (CTGF) expression, at least in part, via myocardin-related transcription factors (MRTFs; MRTF-A and MRTF-B). Recently, TGFβ1 has also been reported to be involved in MRTFs pathway, however, the precise mechanisms how TGFβ1-MRTFs signaling contributes to the regulation of renal fibroblast activities through focal adhesion remain to be investigated.

Methods

In this study, we focused on the effects of TGFβ1 signaling on the activities of renal fibroblasts, especially through MRTFs signaling. Cultured renal fibroblasts were used to examine the activation of MRTFs signaling using promoter assays and the expressions of molecules in response to TGFβ1. Renal fibroblasts were transfected with either siRNA targeting MRTFs or focal adhesion components to determine the impact of MRTFs-focal adhesion on renal fibroblast biologies.

Results

Promoter assay showed the activation of MRTFs signaling by TGFβ1 in a dose- and a time-dependent manner in renal fibroblasts. The stimulation of renal fibroblasts with TGFβ1 increased CTGF expression, while siRNA treatment targeting MRTFs suppressed it. In addition, TGFβ1 enhanced fibronectin, various integrins (αv, β1 and β5) and cytoskeletal proteins such as zyxin and talin, all of which were MRTFs-dependent. The treatment of renal fibroblasts with integrin αv siRNA or integrin-linked kinase inhibitor attenuated CTGF expression in response to TGFβ1. Finally, TGFβ1 stimulated the proliferation of renal fibroblasts, however, CTGF siRNA treatment suppressed it.

Conclusion

Our results suggest that MRTF signaling mediates renal fibroblast biologies through focal adhesion formation in response to TGFβ1.

Funding

  • NIDDK Support