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Kidney Week

Abstract: PO0603

Crucial Role of STAT6 Signaling in Renal Fibrosis

Session Information

  • CKD Mechanisms - 1
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Jiao, Baihai, University of Connecticut School of Medicine, Farmington, Connecticut, United States
  • An, Changlong, University of Connecticut School of Medicine, Farmington, Connecticut, United States
  • Wang, Yanlin, University of Connecticut School of Medicine, Farmington, Connecticut, United States
Background

Kidney fibrosis is a pathologic characteristic of chronic kidney disease, resulting in progressive loss of kidney function to end-stage kidney failure. We have recently demonstrated that bone marrow-derived fibroblasts contribute to the pathogenesis of kidney fibrosis. In this study, we investigated the role of STAT6 in activation of bone marrow-derived fibroblasts and development of renal fibrosis in folic acid nephropathy.

Methods

To investigate the role of STAT6 in myeloid fibroblast activation and kidney fibrosis, we used STAT6 knockout mice or treated wild-type mice with AS1517499, a STAT6 inhibitor. Wild-type mice treated with vehicle were used as controls. Folic acid was administered at 250 mg/kg intraperitoneally to induce kidney fibrosis. Kidneys were harvested 2 weeks after folic acid injection.

Results

Folic acid injury led to activation of STAT6 in the interstitial cells of the kidney, which was abolished by treatment with AS1517499. Wild-type mice treated with AS1517499 accumulated fewer bone marrow-derived fibroblasts in the kidneys following folic acid injury compared with vehicle-treated mice. AS1517499 treatment significantly inhibited myofibroblast activation, reduced total collagen deposition, and suppressed expression of extracellular matrix proteins after folic acid injury. Compared with wild-type mice, mice with STAT6 deficiency exhibited fewer myeloid fibroblasts and myofibroblasts and expressed less α-SMA protein in the kidneys following folic acid injury. Furthermore, genetic deletion of STAT6 significantly reduced total collagen deposition and ECM protein production in the kidneys with folic acid nephropathy.

Conclusion

Our results demonstrate that STAT6 signaling plays an important role in the activation of bone marrow-derived fibroblasts during the development of renal fibrosis in folic acid nephropathy. AS1517499 may serve as a novel therapeutic agent for the treatment of chronic kidney disease.

Funding

  • NIDDK Support