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Abstract: TH-PO928

Regulation of Renal Fibroblast Migration, Contraction, and Myofibroblast Differentiation by LPA-LPA1 Signaling via Specific G Proteins

Session Information

Category: CKD (Non-Dialysis)

  • 1903 CKD (Non-Dialysis): Mechanisms

Authors

  • Sakai, Norihiko, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Sato, Koichi, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Miyake, Taito, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Sagara, Akihiro, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Kitajima, Shinji, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Toyama, Tadashi, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Hara, Akinori, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Iwata, Yasunori, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Shimizu, Miho, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Furuichi, Kengo, Kanazawa University, Kanazawa, ISHIKAWA, Japan
  • Wada, Takashi, Kanazawa University, Kanazawa, ISHIKAWA, Japan
Background

Renal fibrosis is a common pathway leading to end-stage renal disease regardless of etiologies. Pathologically, tissue fibrosis is characterized by the accumulation of fibroblasts/myofibroblasts and the excessive deposition and contraction of extracellular matrix. We have previously found the lipid mediator lysophosphatidic acid (LPA) and one of its receptors, LPA1, contributes to the development of renal fibrosis. However, the precise mechanisms by which LPA-LPA1 signaling activates renal fibroblasts (RFBs) remain to be determined.

Methods

In this study, we focused on the direct effects of LPA-LPA1 signaling on RFBs biologies, especially migration, contraction and myofibroblast differentiation. Cultured RFBs were used to examine cell migration, cell contraction and the expression of alpha smooth muscle actin (aSMA), a marker for myofibroblast differentiation, in response to LPA. RFBs were transfected with either LPA1 siRNA or control siRNA to determine the impact of LPA1 on RFBs biologies. In addition, we also investigated the involvement of G proteins in the LPA-LPA1 signaling-associated biologies of RFBs.

Results

RFBs treated with control siRNA were attracted by LPA in a dose-dependent manner, whereas LPA did not stimulate LPA1 siRNA-treated RFBs migration. In addition to RFBs migration, we also found that LPA directly induced cell contraction and aSMA gene expression by RFBs dependent on LPA1. To determine the involvement of G proteins in the LPA-LPA1 signaling, RFBs were transfected with siRNAs targeting G proteins. The chemotactic activity of LPA was significantly inhibited by siRNA treatment against Gai class of G proteins. In addition to that, pertussis toxin (an inhibitor of Gai) also blocked LPA-induced migration of RFBs. We also found that LPA-LPA1 signaling enhanced cell contraction and aSMA expression through Ga12/13 class of G proteins.

Conclusion

Our results suggest that LPA-LPA1 signaling directly modulates RFBs biologies dependent on specific G proteins in the pathogenesis of renal fibrosis.

Funding

  • Other U.S. Government Support