Development of Drug Efficacy Testing Platform for Glomerulonephritis

Abstract

We developed a 3D glomeruli tissue chip for glomerulonephritis (GN) testing, featuring a gravity-driven glomerular filtration barrier (GFB) with human podocytes and endothelial cells with a bidirectional flow in the bottom channel. Using puromycin-induced GN, we observed decreased cell viability, increased albumin permeability, and reduced WT1 and nephrin compared to the normal GFB. Tacrolimus restored cell viability, reduced albumin permeability, and increased WT1 expression. Using serum from five membranous nephropathy (MN) patients, we created MN models using a GFB-mimicking chip. A notable decline in cell viability was observed in the serum-induced MN1 and MN2 models. However, tacrolimus restored it. Albumin permeability was reduced in the MN1, MN2, and MN5 models by tacrolimus treatment. MN1 displayed the best clinical response to tacrolimus, exhibiting increased expression of WT1 in chip-based evaluations after tacrolimus treatment. We successfully evaluated the efficacy of tacrolimus using puromycin-induced and serum-induced GN models on a chip that mimicked the structure and function of the GFB. The GFB-mimicking chip holds promise as a personalized platform for assessing drug efficacy using patient serum samples.

Characterizing Glomerular Barrier Dysfunction with Patient-Derived Serum in Glomerulus-on-a-Chip Models: Unveiling New Insights into Glomerulonephritis

“…Thus, we focused on human immortalized CIHP-1 cells known to present a phenotype and function very similar to those of primary podocytes. Most importantly, they can be efficiently differentiated at a large scale without using laborious protocols, as we have previously shown [13]. Our data showed that characteristic podocyte morphology, including long spindle-like projections, fine processes, short rounded projections, and interdigitations between cells, could be observed on day 7 of differentiation.…”

“…Recent advances in kidney-on-a-chip or renal microfluidic device technology have demonstrated great potential for kidney disease modeling and assessment of drug-induced kidney injury by recapitulating in vivo tissue characteristics. A glomerulus-on-a-chip research study reported that a unique culture environment mimicking the in vivo physiological environment can elicit more potential in cultured cells than a conventional static culture [9][10][11][12][13]. Thus, it is a promising tool as an alternative to animal experiments.…”