# Role of macrophages in cisplatin-induced kidney injury and progression to chronic kidney disease

> **NIH NIH F31** · UNIVERSITY OF LOUISVILLE · 2020 · $32,123

## Abstract

Project Summary
Cisplatin is a commonly used chemotherapeutic agent with dose-limiting nephrotoxicity. 30% of patients who
receive cisplatin develop acute kidney injury (AKI), or a rapid decrease in kidney function. Development of AKI
increases the risk of chronic kidney disease (CKD) and mortality. Even patients that do not develop AKI by
clinical standards are still at risk for long term declines in renal function and CKD development. There are
currently no therapies approved to prevent or treat cisplatin-induced kidney injury (CDDP-KI). In the past,
research on CDDP-KI utilized a single, high dose model of injury. This model is lethal to mice within 3-4 days
and does not allow for study of long-term renal outcomes. We have developed a more clinically relevant
repeated low dose cisplatin (RLDC) model of CDDP-KI. In this model, mice receive 4 weekly low doses of
cisplatin and can survive more than 6 months after treatment [1]. This RLDC model has been shown to induce
renal fibrosis and progressive declines in renal function indicative of CKD development [1, 2]. Other models of
kidney fibrosis have demonstrated that macrophages can play a pro-fibrogenic role by differentiating into
myofibroblasts, the main effector of fibrotic development. Our preliminary studies show that the RLDC model
causes accumulation of macrophages and myofibroblasts that persists up to 6 months after treatment. This is
accompanied by a sustained increase in transforming growth factor beta (TGF), which is a mediator of
macrophage to myofibroblast transition. Lastly, we have identified a population of F4/80+ αSMA+ CD206+ cells
that appear after the fourth dose of cisplatin, indicative of this transition state. This research proposal will
examine the relationship between macrophage response and susceptibility to CDDP-KI using our RLDC model
of cisplatin-induced injury. We hypothesize that the repeated low dose cisplatin model promotes fibrosis
and CKD development through stimulating chronic macrophage activity and macrophage to
myofibroblast transition in the kidney. This hypothesis will be tested with the following aims. Aim 1:
Characterize immune response and macrophage to myofibroblast transition during repeated low dose cisplatin.
In this aim, we will use flow cytometry to analyze the immune cell response to cisplatin induced injury in the
kidney. We will also isolate renal macrophages following cisplatin treatment and perform RNAseq to evaluate
development of myofibroblast characteristics. Lastly, we will utilize bone marrow chimera models to determine
if bone marrow derived immune cells are infiltrating the kidney following cisplatin treatment. Aim 2: Determine
the role of macrophages in repeated low dose cisplatin induced fibrosis and chronic kidney disease. In this
aim, we will determine how global depletion of macrophages and inhibition of chemokine (C-C motif) receptor 2
(CCR2) monocyte trafficking affects renal function and development of fibrosis in our RLDC mod...

## Key facts

- **NIH application ID:** 10066843
- **Project number:** 1F31DK126400-01
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** Sophia Marie Sears
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,123
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066843

## Citation

> US National Institutes of Health, RePORTER application 10066843, Role of macrophages in cisplatin-induced kidney injury and progression to chronic kidney disease (1F31DK126400-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066843. Licensed CC0.

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