# Role of Histone Methyltransferase EZH2 in Acute and Chronic Renal Injury

> **NIH NIH R01** · RHODE ISLAND HOSPITAL · 2021 · $361,890

## Abstract

Our long-term goal is to identify key epigenetic regulator(s) that modulate acute kidney injury (AKI) and chronic
kidney disease (CKD). Specifically, we will investigate the role of enhancer of zeste homolog 2 (EZH2), a histone
methyltransferase that acts primarily as a gene silencer, in the pathogenesis of acute and chronic kidney injury
and assess whether pharmacologic and genetic targeting of EZH2 can prevent or ameliorate AKI and CKD. AKI
and CKD are common and costly global health problems. AKI predisposes to CKD; CKD increases the risk of
cardiovascular disease and death. At present, there are no effective therapies for AKI. Current treatments for
CKD retard but not prevent progression to end stage renal disease. Identifying key molecules that mediate and
modulate AKI and CKD is imperative to develop new, more effective therapies to prevent and treat AKI and halt
progression of CKD. In preliminary studies we found that EZH2 is highly expressed in the kidney after acute and
chronic injury and that inhibition of EZH2 with 3-DZNeP attenuates development of renal fibrosis induced by
unilateral ureteral obstruction. This is associated with preservation of PTEN and Smad7 expression and inhibition
of epithelial cell cycle arrest in G2/M phase. Importantly, EZH2 inhibition also improves renal function and
reduces renal tubular cell injury and apoptosis in ischemia/reperfusion (I/R) induced AKI in mice. These data
establish EZH2 activation as a critical factor in the pathogenesis of acute and chronic renal injury. However, the
molecular basis by which EZH2 mediates these pathological processes remains poorly understood. Our central
hypothesis is that upon injury, EZH2 promotes the progression of AKI to renal fibrosis by inducing renal tubular
death and defective renal epithelium repair. Our working hypothesis is that injury to renal tubular cells activates
EZH2 leading to epigenetic repression of multiple genes associated with cell survival, promoting cell death.
Prolonged EZH2 activation in surviving tubular cells results in partial EMT, G2/M arrest, a secretory profibrotic
phenotype by repression of E-cadherin, PTEN and Smad7 and subsequent activation of some profibrotic
signaling pathways such as Smad3. To test this hypothesis, we will first define the role of EZH2 in the
pathogenesis of AKI and progression of AKI to CKD by using more specific EZH2 inhibitors and conditional
knockout mice with EZH2 deleted in renal tubular cells following I/R and folic acid injury; Second, we will elucidate
the mechanism(s) linking EZH2 activation to renal epithelial cell death by examining the relative contributions of
E-cadherin, tissue inhibitor of metalloproteases-3 and Raf-1 kinase inhibitor protein to renal epithelial cell death
in vitro in the presence or absence of EZH2 inhibition. Finally, we will determine the molecular basis of EZH2-
mediated transition of renal epithelial cells to a profibrotic phenotype by examining the relative contributions of
E-ca...

## Key facts

- **NIH application ID:** 10264792
- **Project number:** 5R01DK113256-04
- **Recipient organization:** RHODE ISLAND HOSPITAL
- **Principal Investigator:** SHOUGANG ZHUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $361,890
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10264792

## Citation

> US National Institutes of Health, RePORTER application 10264792, Role of Histone Methyltransferase EZH2 in Acute and Chronic Renal Injury (5R01DK113256-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10264792. Licensed CC0.

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