Epigenetic mechanisms differentially regulate blood pressure and renal dysfunction in male and female Npr1 haplotype mice.

Autor: Kumar P; Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA., Neelamegam K; Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA., Ramasamy C; Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA., Samivel R; Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA., Xia H; Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Kapusta DR; Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA., Pandey KN; Department of Physiology, School of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, USA.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2024 Aug 15; Vol. 38 (15), pp. e23858.
DOI: 10.1096/fj.202400714R
Abstrakt: We determined the epigenetic mechanisms regulating mean arterial pressure (MAP) and renal dysfunction in guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) gene-targeted mice. The Npr1 (encoding NPRA) gene-targeted mice were treated with class 1 specific histone deacetylase inhibitor (HDACi) mocetinostat (MGCD) to determine the epigenetic changes in a sex-specific manner. Adult male and female Npr1 haplotype (1-copy; Npr1 +/- ), wild-type (2-copy; Npr1 +/+ ), and gene-duplicated heterozygous (3-copy; Npr1 ++/+ ) mice were intraperitoneally injected with MGCD (2 mg/kg) for 14 days. BP, renal function, histopathology, and epigenetic changes were measured. One-copy male mice showed significantly increased MAP, renal dysfunction, and fibrosis than 2-copy and 3-copy mice. Furthermore, HDAC1/2, collagen1alpha-2 (Col1α-2), and alpha smooth muscle actin (α-SMA) were significantly increased in 1-copy mice compared with 2-copy controls. The expression of antifibrotic microRNA-133a was attenuated in 1-copy mice but to a greater extent in males than females. NF-κB was localized at significantly lower levels in cytoplasm than in the nucleus with stronger DNA binding activity in 1-copy mice. MGCD significantly lowered BP, improved creatinine clearance, and repaired renal histopathology. The inhibition of class I HDACs led to a sex-dependent distinctive stimulation of acetylated positive histone marks and inhibition of methylated repressive histone marks in Npr1 1-copy mice; however, it epigenetically lowered MAP, repaired renal fibrosis, and proteinuria and suppressed NF-kB differentially in males versus females. Our results suggest a role for epigenetic targets affecting hypertension and renal dysfunction in a sex-specific manner.
(© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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