Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a systemic cardiometabolic syndrome marked by chronic inflammation, endothelial dysfunction, and multi-organ crosstalk. Findings from large clinical trials such as PARAGON-HF, have underscored that renal impairment often precedes overt cardiac dysfunction and strongly predicts adverse outcomes. Despite major clinical advances, the molecular crosstalk translating metabolic stress into renal dysfunction remains elusive, with emerging evidence implicating epigenetic remodeling of chromatin architecture as a key integrator of metabolic and inflammatory signals. Here, we performed deep renal phenotyping in our HFpEF model to dissect how chromatin remodeling reshapes the renal transcriptome and phenotype, with particular focus on the involvement of BET family proteins as potential epigenetic mediators. Method A well-established two-hit mouse model of HFpEF was generated by combining a high-fat diet (60 kcal% fat) with L-NAME in the drinking water (0.5 g/L) for 15 weeks, while control mice received a standad diet (10 kcal% fat) and vehicle. Deep renal phenotyping included functional assessment of plasma creatinine, cystatin C, and galectin-3; structural evaluation through Collagen-1A1 immunostaining and PAS histochemistry; molecular profiling by RNA sequencing and proteomics; and epigenetic mapping using CUT&RUN to delineate chromatin accessibility and the genomic occupancy of BET family members, in particular BRD2 and BRD4. Results HFpEF mice exhibited marked renal impairment, reflected by significant elevations in plasma creatinine, cystatin C, and galectin-3. Histological analysis revealed pronounced tubular injury and interstitial fibrosis. Multi-omic integration of transcriptomic and proteomic datasets identified coordinated activation of pro-fibrotic and inflammatory signaling (TGF-β/SMAD, NF-κB). Epigenomic profiling by CUT&RUN revealed widespread chromatin reorganization with distinct redistribution of BRD2 and BRD4 binding across the genome. Both proteins exhibited strong enrichment at loci regulating TGF-β/SMAD, circadian (BMAL1/Clock), WNT, and PPAR-α signaling. Reactome pathway analysis highlighted convergence of these epigenetic changes on networks controlling extracellular-matrix remodeling, metabolic adaptation, and cell-stress responses. Collectively, these data delineate an epigenetically driven transcriptional program linking chromatin remodeling to lipotoxicity, inflammation, fibrosis, and metabolic stress in the HFpEF kidney. Conclusions BET-mediated epigenomic rewiring drives renal dysfunction in HFpEF. Our integrative molecular pipeline shows that chromatin remodeling by BRD2 and BRD4 shapes kidney programs of inflammation, fibrosis, and metabolic stress. By decoding the HFpEF–kidney axis, these findings outline a mechanistic basis for epigenetic therapies and support targeted interventions in high-risk cardio-renal phenotypes.
Atzemian et al. (Fri,) studied this question.