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Abstract: SA-PO1009

Ablation of the Non-Receptor Tyrosine Kinase c-Abl in Renal Tubular Cells Alleviates Renal Fibrosis in Mice

Session Information

  • CKD: Pathobiology - II
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2203 CKD (Non-Dialysis): Mechanisms

Authors

  • Bao, Qianyi, Department of Gynecology & Obstetrics, Medical School, Southeast University, Nanjing, China
  • Wang, Anyu, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
  • Yuan, Xiao-Dong, Department of Urology, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China
  • He, Lin, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
  • Ma, Gang, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, China
Background

Renal fibrosis is the uppermost symptom of chronic kidney disease (CKD). The renal tubules, particularly the proximal tubule cells (PTCs), are easily damaged and the injured PTCs are associated with the occurrence of CKD. C-Abl (encoded by the Abl1 gene) is a member of the Abelson family of non-receptor tyrosine kinases and plays a fundamental function in organ fibrosis. However, the role of c-Abl in the pathogenesis of PTCs and CKD remains elusive.

Methods

Western blotting and immunofluorescence (IF) were used to determine the expression pattern of c-Abl in clinical samples and fibrotic kidneys from CKD mice treated with unilateral ureteral obstruction (UUO) and unilateral ischemia-reperfusion injury (uIRI). Next, c-Abl was deleted specifically in PTCs by using Ksp-Cre mice to generate Ksp-Cre; c-Ablfl/fl knockout mice which subsequently were treated with UUO and uIRI to obtain fibrosis models to understand the function of c-Abl. The role of c-Abl was further confirmed in human proximal tubule epithelial cells (HK-2 cell line) stimulated with TGF-β1. C-Abl knockout was induced in myofibroblasts to generate aSMA-CreERT; c-Ablfl/fl mice which were treated with UUO and uIRI to determine if targeting c-Abl in myofibroblasts was beneficial in alleviating established renal fibrosis and kidney dysfunction.

Results

The expression and kinase activity of c-Abl were elevated in human and mouse fibrotic kidneys, and were positively correlated with fibrogenic genes. IF staining showed that c-Abl was localized in parenchymal fibroblasts and myofibroblasts, notably enriched in PTCs of fibrotic kidneys. The specific deletion of c-Abl in Ksp-Cre; c-Ablfl/fl mice attenuated renal fibrosis through inhibiting PTCs activation and parenchymal collagen production. In HK-2 cells, c-Abl was shown to be essential and sufficient to induce a-SMA expression and collagen deposition as downstream of TGF-β signaling pathway. Finally, ablation of c-Abl in myofibroblasts in aSMA-CreERT; c-Ablfl/fl mice significantly mitigated the progression of kidney fibrosis in established CKD mouse models.

Conclusion

This study primarily found that c-Abl is involved in renal fibrosis by regulating the activity of PTCs and the production of renal interstitial collagen, implying that c-Abl might be a new target for the prevention and treatment of renal fibrosis in the progression of CKD.

Funding

  • Government Support – Non-U.S.