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Drug-Induced Nephrotoxicity Assessment in 3D Cellular Models

Profile image of Ivan PachonIvan Pachon

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https://doi.org/10.3390/MI13010003
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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 di...

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IRJPMS Editor

IRJPMS, 2025

Drug-induced nephrotoxicity is a significant contributor to acute and chronic kidney injury in clinical and preclinical settings. This review provides an integrative overview of the diverse pathophysiological mechanisms underlying DIN, including hemodynamic al terations, direct tubular toxicity, crystal nephropathy, thrombotic microangiopathy, rhabdomyolysis, interstitial nephritis, and glomeru lonephritis. Evidence from human studies and animal models (primarily rodents) is synthesized, highlighting how various drugs disrupt rena l structure and function. A comprehensive table categorizes nephrotoxic agents, their mechanisms, pathological changes, and clinical manifest ations. Both herbal and synthetic treatments are reviewed in rat and human models. Furthermore, this review explores novel therapeutic str ategies, including mitochondria-targeted therapy, regenerative medicine with stem cell approaches, RNA-based interventions, artificial intelligence, and machine learning for predictive modeling, and the development of kidney-on-a-chip systems. The new technologies would provide successful approaches to detect nephrotoxicity early and understand pharmaceutical mechanisms while delivering individualized care, whic h minimizes traditional animal testing needs and boosts drug development translation .

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Kidney-based in vitro models for drug-induced toxicity testing
Silvia Mihaila

Archives of Toxicology, 2019

The kidney is frequently involved in adverse effects caused by exposure to foreign compounds, including drugs. An early prediction of those effects is crucial for allowing novel, safe drugs entering the market. Yet, in current pharmacotherapy, drug-induced nephrotoxicity accounts for up to 25% of the reported serious adverse effects, of which one-third is attributed to antimicrobials use. Adverse drug effects can be due to direct toxicity, for instance as a result of kidney-specific determinants, or indirectly by, e.g., vascular effects or crystals deposition. Currently used in vitro assays do not adequately predict in vivo observed effects, predominantly due to an inadequate preservation of the organs’ microenvironment in the models applied. The kidney is highly complex, composed of a filter unit and a tubular segment, together containing over 20 different cell types. The tubular epithelium is highly polarized, and the maintenance of this polarity is critical for optimal functionin...

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Development and validation of a new nephrotoxicity model mimicking cell physiology microenvironment
Natalia Sánchez

2017

The kidneys are very efficient organs that perform multiple functions in the body. One of the main functions performed by the kidneys is the elimination of waste products and excess fluid from the body through the urine. The regulation of body salts and acid content are functions played by these organs. In the kidney also takes place the production of different hormones. The kidney is made up of nephrons, which are the structural and functional units of these organs. The nephrons are composed by the following structures: The glomerulus, which is the first part of the nephron, where the plasma is filtered from the blood. Immediately afterward, we find the tubule, which structure is like a long narrow tube, where the filtered fluid from the blood is processed into the urine. The tubule is divided into different segments: proximal tubule, loop of Henle, distal tubule and collecting tube. In this Thesis, we focused on the study of the segment formed by the proximal tubule (PT). The main...

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Primary culture of rabbit proximal tubules as a cellular model to study nephrotoxicity of xenobiotics
Anne Blais

Kidney International, 1993

Primary culture of rabbit proximal tubules as a cellular model to study nephrotoxicity of xenobiotics. The effects of gentamicin treatment on functions of the plasma membrane-bound proteins in situ were investigated in primary culture of rabbit proximal tubular cells (PTC), a recognized model of renal epithelial cells. Activities of apical and basolateral enzymes, activities of phosphate, glucose and alanine sodium-coupled transport systems and leakage of the cytosolic enzyme lactate dehydrogenase (LDH) were determined in FTC grown in glucose-free culture medium as confluent monolayers and incubated with the aminoglycoside. Gentamicin altered in a concentration-and timedependent manner the activity of dipeptidyl peptidase IV (DPP IV), neutral aminopeptidase (NAP), NaK-ATPase and the maX ofsodium-dependent glucose and phosphate uptake, whereas yglutamyltranspeptidase (GGT) and sodium-dependent alanine uptake were unaffected. Identical concentration of gentamicin was required to induce LDH leakage and cell functions impairment. In contrast, under short time exposure, a condition where the enzyme activities were untouched, mercuric chloride inhibited to a similar extent the activity of the three sodium-coupled transport systems. These data suggest that whereas alterations in membrane fluidity might mediate the effects of gentamicin on membrane functions, the inhibition of transports by mercuric chloride rather reflects an effect on sodium permeability of the apical membrane. They also suggest that study of Na-coupled transports in proximal tubular cells grown in primary culture is a simple and sensitive in vitro model to assess drug-induced nephrotoxicity.

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

Polymers

Random electrospun three-dimensional fiber membranes mimic the extracellular matrix and the interfibrillar spaces promotes the flow of nutrients for cells. Electrospun PLGA membranes were analyzed in vitro and in vivo after being sterilized with gamma radiation and bioactivated with fibronectin or collagen. Madin-Darby Canine Kidney (MDCK) epithelial cells and primary fibroblast-like cells from hamster’s cheek paunch proliferated over time on these membranes, evidencing their good biocompatibility. Cell-free irradiated PLGA membranes implanted on the back of hamsters resulted in a chronic granulomatous inflammatory response, observed after 7, 15, 30 and 90 days. Morphological analysis of implanted PLGA using light microscopy revealed epithelioid cells, Langhans type of multinucleate giant cells (LCs) and multinucleated giant cells (MNGCs) with internalized biomaterial. Lymphocytes increased along time due to undegraded polymer fragments, inducing the accumulation of cells of the pha...

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

Frontiers in Pharmacology, 2022

Background: Although doxorubicin (DXR) is one of the most used anticancer drugs, it can cause life-threatening renal damage. There has been no effective treatment for DXR-induced renal damage until now.Aim: This work aims at examining the potential impact of nano-resveratrol (N-Resv), native resveratrol (Resv), and their combination with carvedilol (Card) against DXR-induced renal toxicity in rats and to investigate the mechanisms through which these antioxidants act to ameliorate DXR nephrotoxicity. Method: DXR was administered to rats (2 mg/kg, i.p.) twice weekly over 5 weeks. The antioxidants in question were taken 1 week before the DXR dose for 6 weeks.Results: DXR exhibited an elevation in serum urea, creatinine, renal lipid peroxide levels, endoglin expression, kidney injury molecule-1 (KIM-1), and beclin-1. On the other hand, renal podocin and mTOR expression and GSH levels were declined. In addition, DNA fragmentation was markedly increased in the DXR-administered group. Tre...

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