In a mouse model of cmHFpEF, high-fat diet and L-NAME induced renal dysfunction and epigenomic rewiring, with BET proteins regulating pathways involved in inflammation and fibrosis.
Epigenomic rewiring, particularly involving BET proteins, is a critical orchestrator of cardio-renal impairment in a mouse model of cardiometabolic HFpEF.
Abstract Background Emerging evidence indicates a strong interplay among heart disease, kidney disease, and obesity, leading to complex cardiometabolic phenotypes and poor health outcomes. Cardiometabolic heart failure with preserved ejection fraction (cmHFpEF) is a multi-systemic syndrome characterized by the clustering of metabolic stress, inflammation and cardio-renal impairment. The presence of renal dysfunction in cmHFpEF delineates a high-risk phenotype and amplifies mortality. Understanding cardio-renal interactions in cmHFpEF could pave the way for new mechanism-based interventions. In conditions of cardiometabolic stress, epigenetic remodeling plays a major role by fostering transcriptional alterations and disease phenotypes. In particular, bromodomain and extra-terminal domain (BET) proteins, a family of epigenetic readers, operates as a fine tuner of gene transcription and could be implicated in alterations of the cardio-renal axis. In this study, we aimed to investigate the role of epigenomic and transcriptional alterations as determinants of cardio-renal impairment in cmHFpEF. Method A mouse model of cHFpEF, characterized by the combination of high-fat diet (60 kcal% fat,) and L-NAME in the drinking water (0.5 g/L) for 15 weeks was employed. Control mice received a control diet (10 kcal% fat,) and vehicle in the drinking water. Deep renal phenotyping in control and cmHFpEF mice was performed by: i) renal biomarker profiling (i.e. plasma creatinine, cystatin C, and galectin-3 levels); ii) histological analysis (Collagen 1A1 and Periodic acid-Schiff (PAS) staining); iii) RNA-Sequencing; iv) Proteomics; v) CUT&RUN assay to investigate chromatin accessibility and genome-wide distribution of BET proteins. Results cmHFpEF mice displayed renal dysfunction as assessed by increased creatinine, cystatin C and galectin-3 levels as well as alterations of tissue architecture as shown by Collagen 1A1 and PAS staining (Fig. 1). Bulk RNA-seq and proteomic validation unveiled three top-ranking signals in cmHFpEF vs control kidneys, namely Kynureninase (KYNU), Receptor Accessory Protein 6 (REEP6), and Retinol Dehydrogenase 16 family member 2 (RDH16F2). Analysis of the chromatin landscape by CUT&RUN assays identified increased accessible loci in HFpEF vs control kidneys, with a prominent role of epigenetic readers (BET proteins) in regulating transcriptional programs involved in lipid metabolism, inflammation, circadian rhythm disruption, and fibrosis. This was confirmed by the demonstration of BET protein occupancy (BRD4) on the promoter of genes involved in SMADs, TGF-β, BMAL1 and PPAR-α signaling pathways (Fig. 2). Conclusions Herein we highlight that the epigenomic rewiring is a critical orchestrator of cardio-renal axis in cmHFpEF. These findings set the stage for targeted epigenetic interventions, offering promising avenues to mitigate renal impairment in this high-risk phenotype.
Atzemian et al. (2025) studied Cardiometabolic heart failure with preserved ejection fraction (cmHFpEF). High-fat diet and L-NAME vs. Control diet (10 kcal% fat) and vehicle was evaluated on Renal dysfunction and epigenomic/transcriptional alterations. In a mouse model of cmHFpEF, high-fat diet and L-NAME induced renal dysfunction and epigenomic rewiring, with BET proteins regulating pathways involved in inflammation and fibrosis.