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Abstract: SA-PO274

Development of Drug Efficacy Testing Platform for Glomerulonephritis

Session Information

Category: Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

  • 2000 Pharmacology (PharmacoKinetics, -Dynamics, -Genomics)

Authors

  • Kwon, Eun-Jeong, Seoul National University Bundang Hospital Department of Internal Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
  • Kim, Sejoong, Seoul National University Bundang Hospital Department of Internal Medicine, Seongnam, Gyeonggi-do, Korea (the Republic of)
Background

There was little evidence for the treatment of glomerulonephritis (GN), although the guideline of GN was published. Therefore, we developed drug efficacy testing platform for GN using a 3D glomeruli tissue chip.

Methods

A gravity-driven glomerular-filtration-barrier (GFB) chip was designed with human podocytes and endothelial cells, allowing bi-directional flow in the bottom channel. Puromycin was used to induce glomerulonephritis (GN) models, and serum from membranous nephropathy (MN) patients was used to establish personalized models on the chip. The reproducibility of MN and the effects of tacrolimus were compared with clinical data. RFP-Gendo, WT1, and nephrin, representing the glomerular filtration barrier's molecular structure, were examined. Functional aspects of the GFB, such as cell viability and albumin permeability, were also evaluated.

Results

In the PAN-induced GN model, podocytes exhibited reduced levels of WT1 and nephrin, resulting in decreased albumin permeability and cell viability compared to the standard GFB. However, after the administration of tacrolimus, WT1 expression increased while nephrin expression decreased in the PAN-induced GN model. Tacrolimus also led to a reduction in albumin permeability and restoration of cell viability in this model. MN patients (MN1, MN2, and MN5) who received tacrolimus showed significant improvement. MN1 and MN2 had the most severe pathological injury among the enrolled patients. In the serum-induced MN1 and MN2 models on the chip, there was a significant decrease in cell viability compared to other groups, which was restored after tacrolimus treatment. Additionally, albumin permeability decreased in the MN1, and MN5 models following tacrolimus treatment on the chip. WT1 and nephrin expression increased in after tacrolimus treatment in the case of MN1 model, which had the most favorable response clinically.

Conclusion

The efficacy of tacrolimus was successfully evaluated using PAN-induced and serum-induced GN models on a chip that mimics the structure and function of the GFB. The GFB-mimicking chip holds promise as a personalized platform for assessing drug efficacy using patients' serum samples.

Funding

  • Government Support – Non-U.S.