Butto, Sara, Vidal, Solange, Zeng, Xi Rui, Rausch, Martin, Yasa, Ceren and Ferro, Magali (2025) Engineered 3D kidney glomerular microtissues to model podocyte-centric diseases for the validation of new drug targets. Advanced Healthcare Materials. ISSN 2192-26402192-2659

Abstract

Podocytopathies are a class of kidney diseases characterized by podocyte injury, driving proteinuria, and reduced kidney function. Podocyte injury often disrupts cytoskeletal dynamics and cellular adhesion leading to glomerular dysfunction. The lack of in vitro models truly recapitulating the three-dimensional (3D) organization and tissue mechanics, limits the understanding of podocyte pathophysiology and therapeutic development. Here, we developed 3D microtissues that recapitulate the structure and mechanics of the glomerular filtration barrier, enabling modeling of chemically and genetically induced podocyte injuries for potential new drug target validation. These microtissues replicate the three-layer glomerular structure and hemodynamic-like mechanical stretch, providing an in vitro platform to evaluate disease-relevant mechanobiological signaling, podocyte cytoskeletal dynamics, and adhesion to the basement membrane. We measured collective cellular forces to assess podocyte biochemical resilience in response to genetic or chemical injuries. As a proof-of-concept, we modeled podocyte injury through overexpressing TRPC6 (Transient Receptor Potential Canonical 6), a genetically validated target in podocytopathies, and assessed the therapeutic potential of the inhibitor SAR7334. Our results demonstrated a loss of podocyte contractile forces upon TRPC6 overexpression and recovery following inhibitor treatment, highlighting the potential of glomerular microtissues to model podocyte mechano-pathophysiology and serve as a robust platform for screening new therapies.

Item Type:	Article
Keywords:	Glomerular filtration barrier, 3D cell models, kidney diseases, podocytopathies, target validation
Date Deposited:	08 Jul 2025 00:47
Last Modified:	08 Jul 2025 00:47
URI:	https://oak.novartis.com/id/eprint/55807