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Repeated aminoglycoside exposure activates interferon-stimulated genes in human renal proximal tubular models

Vidya Chandrasekaran1, Tamara Meijer1, Martin O Leonard2

  • 1Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, Amsterdam Institute of Molecular and Life Sciences (AIMMS), De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.

Archives of Toxicology
|July 14, 2026
PubMed

Insights

Aminoglycoside antibiotics like gentamicin and tobramycin cause kidney damage. This study reveals they trigger an innate immune response in human kidney cells, with primary cells showing a clearer response than cell lines.

Area of Science:

  • Nephrology
  • Toxicology
  • Molecular Biology

Background:

  • Aminoglycosides are vital antibiotics, but their use is restricted by nephrotoxicity.
  • The exact cellular mechanisms of aminoglycoside-induced kidney damage are not fully understood.
  • Megalin-mediated proximal tubular accumulation is a known factor, but downstream effects require further investigation.

Purpose of the Study:

  • To compare the transcriptomic responses of various human proximal tubular models to gentamicin and tobramycin.
  • To identify the specific cellular pathways involved in aminoglycoside-induced nephrotoxicity.
  • To determine which in vitro models are most suitable for studying these effects.

Main Methods:

  • Utilized primary proximal tubular epithelial cells (PTEC) and human iPSC-derived proximal tubular-like cells (PTL), alongside RPTEC/TERT1 and HK-2 cell lines.
  • Administered daily doses of gentamicin or tobramycin for seven days.
  • Assessed gene expression using the TempO-Seq EU-ToxRisk v2.1 panel and analyzed data with DESeq2.

Main Results:

  • Primary PTEC and PTL models exhibited strong, coherent transcriptional responses, notably inducing interferon-stimulated genes (ISGs).
  • Key ISGs induced include IFI27, IFI6, IFIT1-3, ISG15, MX1, and OAS1, indicating an innate immune-like response.
  • Tobramycin generally elicited a stronger transcriptional response than gentamicin; RPTEC/TERT1 and HK-2 cells showed less consistent results.

Conclusions:

  • Repeated aminoglycoside exposure induces a significant innate immune-like transcriptional signature in human proximal tubular cells.
  • Primary PTEC and PTL models are more informative for investigating the mechanisms of aminoglycoside nephrotoxicity compared to RPTEC/TERT1 and HK-2 cells.
  • The findings highlight the role of interferon signaling pathways in aminoglycoside-induced kidney damage.
Keywords:
AminoglycosidesiPSCinterferonmegalinproximal tubule

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