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Kidney Week

Abstract: SA-PO1184

A Cost-Effective, High-Throughput, Three-Dimensional Coculture Model of Kidney Fibrosis for Drug Discovery

Session Information

  • CKD: Mechanisms - 3
    October 26, 2024 | Location: Exhibit Hall, Convention Center
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2303 CKD (Non-Dialysis): Mechanisms

Authors

  • Nguyen, Long The, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia
  • Saad, Sonia, Kolling Institute of Medical Research, St Leonards, New South Wales, Australia
  • Pollock, Carol A., Kolling Institute of Medical Research, St Leonards, New South Wales, Australia

Group or Team Name

  • Renal Research Group.
Background

Acute kidney injury (AKI) can cause permanent damage to the kidneys, leading to chronic kidney disease (CKD). Recent advances in system biology revealed thousands of novel molecules involved in the transition of AKI to CKD. Nevertheless, there is a lack of efficient and reliable platforms to validate their biological functions and therapeutic potentials. Stem cell-derived kidney organoids and three-dimensional (3D) tissue culture have been shown to be able to capture key characteristics in kidney development and pathology. However, most of these models are not suitable for studying fibrosis, the common hallmark in CKD. The aim of this study is to develop a cost-effective and high throughput 3D coculture model of kidney fibrosis for drug screening.

Methods

Renal proximal tubular epithelial cells, fibroblasts and endothelial cells were seeded on polymerised Matrigel at a specific ratio to form a 3D network of vascularised tubules with interspersed fibroblasts. The 3D coculture was treated with Transforming Growth Factor beta (TGFb) and Cyclosporin A (CsA) simultaneously to induce AKI and fibrosis. Telmisartan was used as the standard therapy to attenuate these effects.

Results

The 3D coculture produced a stable tubular network that is rich in Collagen type 1A (COL1A), which was otherwise not expressed in 2D and 3D monocellular culture even when being stimulated by TGFb, suggesting that the addition of fibroblasts was essential for fibrotic responses. TGFb and CsA treatment for 48 hours induced cell death to the tubular cells while stimulated cell growth of fibroblasts. In association, the expression of inflammatory markers MCP-1 and TNFa as well as fibrotic markers Fibronectin and COL1A were significantly increased. Such effects were partially attenuated by treatment of telmisartan, suggesting that the 3D coculture mimics pathology and drug responses in patients with kidney diseases.

Conclusion

In conclusion, We have successfully developed a 3D coculture model of tubulointerstitial fibrosis to be used as a low-cost, high throughput fibrotic assay for studying intercellular interaction and drug effects.