# Kidney Injury Molecule-1 in Epithelial Repair

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $457,318

## Abstract

Kidney injury molecule-1 (KIM-1) is the most upregulated protein in proximal tubular epithelial cells in various
states characterized by epithelial cell dedifferentiation: ischemia, toxic renal injury, and renal cell carcinoma.
We have cloned, generated cells and animals expressing wild-type and mutant KIM-1, as well as monoclonal
and polyclonal antibodies to human, mouse, rat, pig, dog, and zebrafish KIM-1. The KIM-1 ectodomain is
cleaved and found in the urine of patients with acute kidney injury (AKI) and chronic kidney disease (CKD),
serving as a sensitive and specific kidney injury biomarker of injury, qualified by the FDA for preclinical safety
studies, and currently used in many clinical safety studies. We have discovered that KIM-1 transforms kidney
epithelial cells into semiprofessional phagocytes making it the first nonmyeloid phosphatidylserine receptor.
We have described a novel KIM-1-mediated phagocytosis pathway by which autophagy regulates
phagocytosis and MHC-restricted antigen presentation in epithelial cells. While KIM-1 expression in AKI is
adaptive, a transgenic mouse which expresses KIM-1 in the renal tubule develops CKD with severe fibrosis,
secondary hypertension, and cardiac hypertrophy. A mutant mouse lacking the extracellular mucin domain,
important for phagocytosis, is protected against development of fibrosis. We have found that KIM-1 internalizes
albumin-bound fatty acids and oxidized lipoproteins which induce a DNA-repair response (DDR) and trigger
profibrotic factor production. We have demonstrated that the DDR leading to G2/M cell cycle arrest is an
important contributor to a senescence–associated profibrotic secretory phenotype. The goal of this proposal is
to further characterize the functional role of KIM-1 during chronic kidney injury. We hypothesize that
persistent KIM-1 signaling activates a proliferative response as well as a DDR leading to G2/M arrest
and a prosecretory fibrotic phenotype. KIM-1-ligand interactions lead to altered cell-matrix interactions
leading to enhanced TGFβ activation. Finally with persistent KIM-1 expression a state of autophagy
insufficiency is generated resulting in GATA activation and an additional non-DDR dependent fibrotic
response. In Specific Aim 1 we will evaluate whether KIM-1-induced mTOR activation leads to
dedifferentiation and proliferation which, together with G2/M arrest due to the DDR, results in a profibrotic
secretory phenotype. In Specific Aim 2 we will evaluate whether the upregulation of ECM components by
KIM-1 expression promotes activation of TGFβ and YAP-induced entry into the cell cycle which, in the setting
of the DDR, potentiates kidney fibrosis. In Specific Aim 3 we will determine whether an impaired autophagic
response associated with uptake of endocytic ligands by KIM-1 triggers the activation of GATA4, DNA damage,
senescence and G2/M arrest. There are therapeutic implications for our studies since agents that interfere
with mTOR, fibronectin, or the HIP...

## Key facts

- **NIH application ID:** 9924518
- **Project number:** 5R01DK072381-14
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** JOSEPH VINCENT BONVENTRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $457,318
- **Award type:** 5
- **Project period:** 2005-06-01 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924518

## Citation

> US National Institutes of Health, RePORTER application 9924518, Kidney Injury Molecule-1 in Epithelial Repair (5R01DK072381-14). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9924518. Licensed CC0.

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