Epigenetic histone modifications play essential roles in regulating chromatin accessibility and gene expression. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of Polycomb Repressive Complex 2, establishes the repressive H3K27me3 mark to silence gene transcription. Although disturbances in tubular H3K27me3-associated pathways have been linked to altered sodium handling and hypertension, how loss of tubular EZH2 affects renal and vascular physiology remains unclear. In this study, we investigated whether tubular EZH2 deletion alters renal function and vascular compliance using a tamoxifen-inducible, renal tubular cell-specific EZH2 gene knockout (EZH2 cKO) mouse model. First, we confirmed efficient knockout of EZH2 and a reduction of H3K27me3 in male mice. EZH2 cKO mice exhibited increased daily urine output and sodium excretion, indicating impaired tubular sodium and water handling. Consistent with these functional changes, transporter analysis demonstrated reduced NHE3, NKCC2, ENaC, and AQP2 expression by Western blot. Proximal and distal tubular cells isolated from EZH2 cKO mice disrupted cell proliferation and decreased PCNA expression. Histological assessment revealed tubular lumen dilatation with epithelial cell flattening and decreased glomerular tuft area, consistent with early structural remodeling that may impair epithelial cell function. Despite these structural alterations, glomerular filtration rate and urine albumin-to-creatinine ratio remained unchanged, indicating preserved glomerular function. EZH2 cKO mice also developed increased pulse wave velocity and reduced arterial compliance without changes in blood pressure, suggesting BP-independent vascular stiffening. Together, tubular EZH2 deletion was associated with compromised renal epithelial transport and arterial compliance. Future studies are needed to determine the mechanisms that mediate EZH2 deficiency-induced renal and vascular dysfunction. This work was supported by 1R01 DK138872, R01HL154147, and R01AG062375 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Shao et al. (Fri,) studied this question.