Sex and Age Differentially Regulate Epigenetic Modifications and Renal Injury Markers in Mice

Abstract

Elucidation of epigenetic mechanism associated with aging renal physiology may reveal potential biomarkers and therapeutic targets for reversing aging renal pathologies. There is a sex difference in the age of onset of renal and cardiac disease, where females are protected against age related changes, including hypertension and fibrosis, until menopause. We hypothesized that sex and age would differentially regulate epigenetic modifications and renal physiology. To test this hypothesis, we examined kidney tissue and serum from 4-month (4M), 12-month (12M), and 24-month (24M)-old male and female C57BL/6JN mice (National Institute of Aging). Renal histone deacetylase (HDAC) and histone acetyltransferase (HAT) activities (ELISA) were significantly higher in all male mice groups compared with age-matched females. However, HAT activity decreased significantly in 24M males compared with 4M males and exhibited sex differences with 24M males having higher (p < 0.05) activity that 24M females. Levels of histone 3 (H3) acetylation at lysine (K) 9 and 27 and methylation at K9 were comparable in all male and female groups. Nonetheless, age and sex differences were observed in H3K27 methylation levels with 24M males having significantly higher (p < 0.05) levels as compared with 24M female mice. Serum creatinine (sCr) levels exhibited significant interaction between age and sex (p < 0.0001). Aging significantly increased sCr levels in 24M mice compared with 4M mice in both sexes. However, sex-differences were evident in sCr levels with 24M female mice having higher levels compared with their age matched male counterparts. Of note, serum levels of kidney injury molecule-1 (KIM-1), a tubule injury biomarker were significantly higher in 24M mice compared with 4M and 12M sex-matched mice (male 24M, 410.1 ± 94.6 vs. 12M, 53.6 ± 17.2 and 4M, 27.9 ± 2.0; pg/ml, p < 0.001; female 24M, 358.3 ± 56.1 vs. 12M, 63.8 ± 13.3 and 4M, 28.2 ± 5.0; pg/ml, p < 0.001). Histones are released in the extracellular space during disease state, act as damage-associated molecular pattern molecules and activate inflammatory pathways. In the serum, circulating histone H3 levels showed significant interaction with age and sex (p < 0.05) and increased significantly with age in both sexes. The data demonstrate that aged female mice exhibited higher levels of serum Cr and KIM-1 whereas aged males have higher KIM-1 levels as compared to sex matched young mice. Sex differences were observed in HDAC and HAT activity with males having higher enzymatic activity as compared to females. These findings will have important implications in age-related renal injury as aging is a primary risk factor for hypertension and related renal disease in men and women. Supported by the NIH grant R03AG075396. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.