# New mouse model of cisplatin-induced AKI and development of prevention therapy

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $531,973

## Abstract

SUMMARY
Cisplatin is among the most widely used drugs against solid tumors, but it can cause severe damage of renal
tubulointerstitial tissues, manifesting itself pathologically in the form of glomerular filtration rate reduction, hype-
ruricemia, hypokalemia, and accelerated secondary glomerulosclerosis and glomerular ischemia. The end re-
sult is acute kidney injury (AKI). Cisplatin induces AKI, which afflicts 25% of cisplatin-treated cancer patients
worldwide. With few exceptions, there is no effective preventive or post-exposure therapy for cisplatin-induced
AKI (C-AKI). Oxidative stress and mitochondrial damage are drivers of AKI-associated pathology; however, the
molecular pathways that mediate these events are poorly defined. Using murine C-AKI model kidney and bi-
opsy samples from C-AKI patients, we have recently found that both oxidative stress and mitochondrial dam-
age are associated with upregulation of renal apurinic/apyrimidinic endonuclease 2 (APE2). In preliminary ex-
periments, we discovered that cisplatin exposure in vivo increases expression of APE2 in mice and inhibits the
action of the protein myosin heavy chain 9 (MYH9), a key regulatory molecule of kidney function. These altera-
tions translate into impact on tubulointerstitial tissue. Our overall working hypothesis is that cisplatin alters
kidney APE2 signaling, leading to inhibition of MYH9 with concomitant tubulointerstitial damage. Here we pro-
pose to more precisely illuminate the target role of APE2 in AKI development, and specifically hypothesize
(i) that highly expressed APE2 affects mtDNA integrity and MYH9/actin intermediate mitochondrial fission and
(ii) that this in turn promotes renal injury by triggering cell-death pathways. To address these dual issues, we
propose using APE2 transgenic and knockout (KO) mouse models to pursue the two Specific Aims detailed
below. In Aim 1, we will validate a genetically engineered murine model of APE2 with direct clinical relevance
to C-AKI. We will comprehensively define the APE2 mouse phenotype and compare it with that of the C-AKI
mouse model and the human C-AKI signature with respect to pathophysiological features at the molecular
level using whole genomic, transcriptional, and immunomic approaches. We will define the binding site of
APE2/MYH9 and its functional significance for further translational studies. In Aim 2, we will conduct proof-of-
concept studies on APE2 targeted therapy for prevention of C-AKI. Additionally, we will define a novel targeted
therapy to prevent nephrotoxicity by delivering APE2 gapmer antisense oligonucleotides or small-molecule in-
hibitors to selectively suppress APE2 expression in proximal tubule cells in APE2 transgenic and C-AKI mice.
Impact: Accomplishing these Specific Aims will be the first step toward constructing a temporal-mechanistic
map of events that occur upon cisplatin exposure and translate into tubulointerstitial nephritis and may ulti-
mately enable development of novel tar...

## Key facts

- **NIH application ID:** 10458002
- **Project number:** 5R01CA251141-02
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Jianjun Zhao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $531,973
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10458002

## Citation

> US National Institutes of Health, RePORTER application 10458002, New mouse model of cisplatin-induced AKI and development of prevention therapy (5R01CA251141-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10458002. Licensed CC0.

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