# Prevention and Treatment of Antibiotic-Induced Acute Kidney Injury Using an Unbiased Gene-Screen Strategy

> **NIH NIH F30** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2021 · $51,036

## Abstract

Gentamicin and vancomycin are nephrotoxic antibiotics that are a major cause of drug-induced acute kidney
injury (AKI), an abrupt and potentially fatal loss of kidney function. AKI occurs in nearly 30% of exposed
patients and increases healthcare costs by causing substantial morbidity and mortality. The lack of a unifying
mechanism for proximal tubule cell injury, a major target for damage, complicates the discovery of effective
therapeutic agents. The goal of this project is to discover the signals that mediate antibiotic-induced proximal
tubule cell injury and to re-purpose existing therapeutic reagents. We hypothesize that computational analysis
of an unbiased, broad-based shRNA screen will identify the “best fit” mechanism(s) of antibiotic-induced AKI
and that mechanistically-targeted drugs will ameliorate renal cell injury and AKI. Preliminary shRNA screening
of gentamicin-exposed human proximal tubule cells detected 226 differentially expressed signal genes.
Pathway analysis of these signal genes identified the Unfolded Protein Response (UPR) as the “best fit”
mechanism of gentamicin-induced cellular injury and guided the selection of several potentially therapeutic
drug targets. The Unfolded Protein Response (UPR) is a mechanism that integrates stress-induced protein
misfolding with protein degradation, mitochondrial injury and cell death. Preliminary data confirmed that
gentamicin exposure caused enhanced protein ubiquitination (a marker of protein degradation), luciferase
dysfunction, mitochondrial fragmentation, decreased ATP content and death of human proximal tubule
epithelial cells. Chemical induction of Hsp70, a protective chaperone protein that regulates UPR at a
proximate step, markedly reduced protein ubiquitination, prevented mitochondrial fragmentation, and
dramatically improved human renal cell survival. In this proposal, we intend to use this methodology to
describe the mechanism of vancomycin-induced AKI, to identify effective therapeutics that prevent
vancomycin-induced injury and to determine the extent of protection in an in-vivo vancomycin model. We also
intend to continue mechanistically-focused experiments to determine the extent of UPR pathway
manipulations in our in vivo models of antibiotic-induced AKI. In-vivo measures of the UPR pathway activation
will be correlated with urinary biomarkers, BUN and cystatin c, histologic injury score, inflammation and animal
survival. This strategy provides a rational approach to identifying targeted therapeutics by combining unbiased
genetic screening and computational analysis with in-vitro and in-vivo pharmacologic manipulations. Our
strategy identifies UPR as a unifying mechanism of gentamicin-induced proximal tubule cell injury, identifies
a UPR-targeted drug that improves cell survival after injury and has the potential to identify both mechanisms
and therapeutics for vancomycin-induced injury.

## Key facts

- **NIH application ID:** 10093025
- **Project number:** 5F30DK117612-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Chinaemere Igwebuike
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $51,036
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10093025

## Citation

> US National Institutes of Health, RePORTER application 10093025, Prevention and Treatment of Antibiotic-Induced Acute Kidney Injury Using an Unbiased Gene-Screen Strategy (5F30DK117612-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10093025. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*