Engineered renal tissue as a potential platform for pharmacokinetic and nephrotoxicity testing

Abstract

Pharmacology and regenerative medicine interact in two ways. One is the use of drugs to promote tissue regeneration. The other, less obvious but with great potential, is the use of techniques developed for regenerative medicine to engineer realistic human organoids for drug screening. This review focuses on testing for nephrotoxicity, often a problem with drugs and poorly predicted in animals. Current human-based screens mainly use proximal tubule cells growing in 2D monolayers. Realism might be improved by collagen-based culture systems that encourage proximal tubule cells to grow as tubules. More realistic would be a recently developed technique for engineering functioning 'mini-kidneys' from suspensions of stem cells, a technique that works in mouse but that could also be applied to humans.

Figure[s10] 1

Routes of uptake of drugs into cells of the renal proximal tubule (simplified to show only major paths). Organic anions and cations are transported across cell membranes by the proteins of the organic anion transporter (OAT) and organic cation transporter (OCT) (SLC22) family of transporters, which have differing (poly) specificities and different expression patterns on the apical and basal sides of cells, thus driving vectorial transport. These exchange import of organic anions for export of ketogluratate and similar molecules, the transmembrane gradient of which is established by other processes that are powered, ultimately, by the Na/K ATPase. The imported anions and cations exit either passively or via active exchangers such as P-glycoprotein. If no efficient exit route exists, either for the imported molecule or its metabolites, there is a risk the cytoplasmic concentrations will become toxic. Small proteins and other molecules, such as aminoglycosides, are recovered from the luminal space by endocytosis driven by the megalin – cubulin system. Some organic cations (such as choline) are also recovered from the lumen by various transport systems [35].

Figure[s11] 2

Production of ‘ mini-kidney ‘ from mouse renogenic stem cells, which are re-aggregated in the temporary presence of Rho kinase (ROCK) inhibitors to protect them from apoptosis. The mini-kidneys can connect with vascular systems either in ovo or in vivo, and will filter tracer molecules from blood.