Drug-Induced Nephrotoxicity Assessment in 3D Cellular Models

Abstract

The kidneys are often involved in adverse effects and toxicity caused by exposure to foreign compounds, chemicals, and drugs. Early predictions of these influences are essential to facilitate new, safe drugs to enter the market. However, in current drug treatments, drug-induced nephrotoxicity accounts for 1/4 of reported serious adverse reactions, and 1/3 of them are attributable to antibiotics. Drug-induced nephrotoxicity is driven by multiple mechanisms, including altered glomerular hemodynamics, renal tubular cytotoxicity, inflammation, crystal nephropathy, and thrombotic microangiopathy. Although the functional proteins expressed by renal tubules that mediate drug sensitivity are well known, current in vitro 2D cell models do not faithfully replicate the morphology and intact renal tubule function, and therefore, they do not replicate in vivo nephrotoxicity. The kidney is delicate and complex, consisting of a filter unit and a tubular part, which together contain more than 20 different cell types. The tubular epithelium is highly polarized, and maintaining cellular polarity is essential for the optimal function and response to environmental signals. Cell polarity depends on the communication between cells, including paracrine and autocrine signals, as well as biomechanical and chemotaxis processes. These processes affect kidney cell proliferation, migration, and differentiation. For drug disposal research, the microenvironment is essential for predicting toxic reactions. This article reviews the mechanism of drug-induced kidney injury, the types of nephrotoxicity models (in vivo and in vitro models), and the research progress related to drug-induced nephrotoxicity in three-dimensional (3D) cellular culture models.

3D proximal tubule-on-chip model derived from kidney organoids with improved drug uptake

“…When cultured in two-dimensions (2D), proximal tubule epithelial cells (PTECs) typically exhibit loss of polarization and function due to limited transporter expression in the absence of physiologic cues induced by extracellular matrices and fluid flow. To overcome these limitations, considerable effort has been devoted to developing more predictive 3D models of nephrotoxicity 6 – 9 . Tubular networks of PTECs grown within a 3D matrigel environment form highly differentiated tubules that respond more sensitively to known nephrotoxins compared to PTECs cultured in 2D 10 .…”

Nano-Resveratrol: A Promising Candidate for the Treatment of Renal Toxicity Induced by Doxorubicin in Rats Through Modulation of Beclin-1 and mTOR

“…It is well known that, due to the role of the kidney in the excretion of exogenous compounds, it is often involved in the adverse effect and toxicity induced by these agents. Drug-induced nephrotoxicity is triggered by various mechanisms including glomerular hemodynamics, inflammation, and disruption of functional protein expression levels (Yu, et al, 2022). Podocin is a critical component of the slit diaphragm in the glomerular filtration barrier (Serrano-Perez et al, 2018).…”

In Vitro and In Vivo Cell-Interactions with Electrospun Poly (Lactic-Co-Glycolic Acid) (PLGA): Morphological and Immune Response Analysis

“…In fact, biodegradable electrospun membranes constituted by thin fibers have been shown to promote cell adhesion, migration and proliferation [ 11 , 29 , 35 ]. In this sense, our team arouses the hypotheses that the fibronectin-coated electrospun PLGA membranes used in the present study should contribute to cell proliferation due to its biomimetic properties, since it has been shown in a previous study that gingival fibroblasts can adhere and proliferate when seeded onto collagen or PLGA substrates [ 36 ].…”