In vitro 3D modeling of the human renal proximal tubule for nephrotoxicity assessment

Authors

• K Wagh
• DA Stavreva
• RAM Jensen
• V Paakinaho
• G Fettweis
• RL Schiltz
• S Mandrup
• DM Presman
• A Upadhyaya
• GL Hager

Abstract

Nephrotoxicity is a major cause of kidney disease, a reason for drug development failure, and a challenge for chemical risk assessment in humans. Historically, tools for nephrotoxicity assessment consisted of 2D monocultures of undifferentiated cells and mammalian animal models. However, due to a limited ability to recapitulate fundamental aspects of human kidney physiology, these systems often fail to predict nephrotoxicity. Proximal tubule (PT) cells are the most frequent site of damage as they transport and metabolize xenobiotics, leading to intracellular accumulation of reactive metabolites, which can impair PT solute reabsorption and disrupt essential nutrient homeostasis, causing negative health effects.

In vitro systems that mimic key aspects of human PT physiology hold the potential to better model and predict nephrotoxicity. Here, we introduce two advanced in vitro systems that we have developed to address unique aspects of nephrotoxicity assessment: (1) screening level system – designed to create interpretive context for decision making by efficient survey of chemicals – consisting of self-organizing, lumen-forming, free-floating 3D microtissues of human PT cells that develop tubular structures, express transporters, and demonstrate enhanced differentiated longevity and sensitivity to nephrotoxic compounds compared to 2D cultures. (2) Microphysiological system integrating microfluidics with co-cultures of human-derived cells and tissue engineering to create 3D microenvironments that mimic in vivo functions and dynamics. Biologically relevant flow rates promote barrier function and transporter activity. Both screening level systems and microphysiological systems are integral to address contemporary challenges of new approach methodologies (NAMs)-based risk assessments.

Scientific Focus Area: Clinical Research

This page was last updated on Monday, September 25, 2023