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Human kidney on a chip assessment of polymyxin antibiotic nephrotoxicity.
- Source :
-
JCI insight [JCI Insight] 2018 Dec 20; Vol. 3 (24). Date of Electronic Publication: 2018 Dec 20. - Publication Year :
- 2018
-
Abstract
- Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques - including human microphysiological systems, or "organs on chips" - are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.22 ×10-16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)-like 2 pathway, despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as a potentially novel pathway for PMB-induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule.
- Subjects :
- Animals
Anti-Bacterial Agents toxicity
Biomarkers
Dehydrocholesterols
Desmosterol
Disease Models, Animal
Gene Expression
Heme Oxygenase-1
Hepatitis A Virus Cellular Receptor 1
Humans
Kidney metabolism
Kidney Tubules, Proximal drug effects
Lanosterol
NF-E2-Related Factor 2 metabolism
Polymyxin B pharmacology
Polymyxins pharmacology
Acute Kidney Injury chemically induced
Kidney drug effects
Polymyxins toxicity
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 3
- Issue :
- 24
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 30568031
- Full Text :
- https://doi.org/10.1172/jci.insight.123673