Abstract: PO1705
DNA Double-Strand Breaks of Human Glomerular Endothelial Cell-Induced Collagen Type VI Excretion and Nodular Lesions in Various Kidney Diseases
Session Information
- Glomerular Diseases: Fibrosis and Extracellular Matrix
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1201 Glomerular Diseases: Fibrosis and Extracellular Matrix
Authors
- Fujii, Ai, Kanazawa Medical University School of Medicine, Department of Nephrology, Kahokugun, Japan
- Sunatani, Yumi, Kanazawa Medical University School of Medicine, Department of Biochemistry, Kahokugun, Japan
- Furuichi, Kengo, Kanazawa Medical University School of Medicine, Department of Nephrology, Kahokugun, Japan
- Fujimoto, Keiji, Kanazawa Medical University School of Medicine, Department of Nephrology, Kahokugun, Japan
- Adachi, Hiroki, Kanazawa Medical University School of Medicine, Department of Nephrology, Kahokugun, Japan
- Iwabuchi, Kuniyoshi, Kanazawa Medical University School of Medicine, Department of Biochemistry, Kahokugun, Japan
- Yokoyama, Hitoshi, Kanazawa Medical University School of Medicine, Department of Nephrology, Kahokugun, Japan
Background
Collagen deposition is the common histological end-point of progressive chronic kidney diseases (CKDs). We focused on collagen type VI (COL6) which is known as components of nodular lesions. This study was performed to test the hypothesis that glomerular endothelial cells with DNA double-strand breaks (DSBs) induce the accumulation of COL6 in various kidney disease and evaluated the mechanism of COL6 accumulation after DSBs.
Methods
We examined various kidney diseases (n:180) in which DSBs and glomerular fibrosis were detected by phospho-histone H2AX (γ-H2AX) expression and COL6 accumulation. In vitro study, we investigated the relationship between DSBs and COL6 excretion and the intracellular signal pathways in human glomerular endothelial cells (HRGECs) using mitomycin C (MMc)-induced DNA damage, and other two agents; Neocarzinostatin (NCS) and camptothecin (CPT). We examined the effect of DSBs response signal pathways, i.e. ATM, ATR and DNA-PK using their specific kinase inhibitors (KU55933, VE-821, Nu7441).
Results
COL6 and γ-H2AX were detected in glomeruli in which the γ-H2AX-positive area was identified as the independent factor for the % COL6-positive area (β: 0.553, t = 2.842, p = 0.009). Furthermore, COL6 was a component of the nodular lesions found in various kidney diseases. In vitro study of MMc-induced DNA damage, COL6 excretion detected by the decrease of COL6 positive cells was suppressed in the ATR-inhibited group (p <0.01 for 2 h, p <0.001 for 24 h). Moreover, CPT treated cells induced the COL6 excretion as well as MMc treated cells (p <0.001 for MMc, p=0.002 for CPT).
Conclusion
This study showed that DNA damage-sensing kinase of ATR was activated in response to DSBs and induced COL6 secretion of human glomerular endothelial cells. Furthermore, DNA damage may induce the nodular glomerulosclerosis in various kidney diseases.
Funding
- Government Support - Non-U.S.