# Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin.

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2022 · $223,694

## Abstract

Nephrotoxicity is a primary dose-limiting toxicity for cisplatin, a potent first-line therapy for many solid
malignancies. The mechanistic basis for cisplatin-induced kidney damage is not fully understood and no efficient
management strategies are currently available. The endocannabinoid (EC) system, which has been initially
focused on the central nervous system, also plays important roles in the peripheral organs, including the kidneys.
The most well-characterized ECs are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). The biosynthesis
of AEA is through the hydrolysis of N-arachidonoyl-phosphatidyl-ethanolamines via at least three distinct
biosynthetic routes. The 2-AG is produced by diacylglycerol lipases, which hydrolyze 2-arachidonoyl-containing
diacylglycerols (DAG) to generate 2-AG. After production, ECs bind to the local cannabinoid receptors (CB1 and
CB2) in an autocrine or paracrine manner. It has been shown that EC system participates in different kidney
diseases, including cisplatin-induced nephrotoxicity (CIN), and that interventions of CB receptors are promising
therapeutic strategies. Surprisingly, majority of studies focus on CB receptors, and little is known about roles of
ECs metabolic enzymes in kidney damages. It is important to address this significant gap and imperative to
investigate the role of ECs enzymes in kidney diseases. A recent study showed that in cisplatin-treated mice,
AEA was significantly increased while 2-AG had no change in the kidneys and that inhibition of CB1 receptors
attenuated the cisplatin-induced renal dysfunction, suggesting that endocannabinoid system through CB1
receptors promotes cisplatin-induced kidney injury. We initially intended to test whether FAAH inhibition, which
results in increased levels of AEA, would aggravate the CIN. Surprisingly, CIN was dramatically attenuated in
FAAH KO mice, suggesting that the increased levels of AEA is actually protective in CIN. The elevation of AEA
levels after FAAH inhibition could also result in reduced levels of AEA-FAAH-derived arachidonic acid (AA) and
increased levels of AEA-COX2-derived prostamides. Our preliminary data demonstrated that the protection by
FAAH inhibitor was reversed by the substrate-selective COX2 inhibitor LM4131 (inhibits AEA-COX2, not AA-
COX2), but not by the supplementation of AA, nor the blocking CB receptors. Based on the above information,
the hypothesis to be tested is that FAAH inhibition protects the kidneys against CIN via AEA-COX2-derived
prostamides. The following Aims are proposed to test the hypotheses. Aim 1: To determine whether inhibition
of FAAH protects the kidneys against CIN. Studies will use genetic and pharmacological as well as both systemic
and kidney-targeted approaches for FAAH inhibition. Aim 2: to determine whether AEA-COX2-derived
prostamides are the downstream signaling pathway responsible for the renoprotection after FAAH inhibition in
CIN. Aim 3: To establish that inhibition of FAAH will not inter...

## Key facts

- **NIH application ID:** 10513011
- **Project number:** 1R21CA274012-01
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Ningjun Li
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $223,694
- **Award type:** 1
- **Project period:** 2022-08-16 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10513011

## Citation

> US National Institutes of Health, RePORTER application 10513011, Inhibition of fatty acid amide hydrolase as a novel strategy to prevent nephrotoxicity of cisplatin. (1R21CA274012-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10513011. Licensed CC0.

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