Chromatin rewiring orchestrates a reno-cardial axis in HFpEF

Introduction Heart failure with preserved ejection fraction (HFpEF) is a major and rapidly increasing global health burden driven by ageing, obesity, and cardiometabolic comorbidities. Lifestyle and environmental exposures play a central role in HFpEF pathogenesis and exert long-lasting effects through epigenetic mechanisms. However, whether epigenetic regulation contributes to renal dysfunction, a key determinant of prognosis in HFpEF, remains largely unexplored. Methods An established two-hit mouse model of HFpEF was generated by combining a high-fat diet (60 kcal% fat) with L-NAME in drinking water (0.5 g/L) for 15 weeks. Controls received a normal diet (10 kcal% fat) and a vehicle. Comprehensive renal phenotyping included: (i)functional assessment using direct in vivo measurement of renal clearance via a transdermal GFR device, together with plasma creatinine, cystatin C, galectin-3, and uremic toxins;(ii) structural analysis by H&E, Masson’s trichrome, and PAS staining; iii) molecular profiling by RNA sequencing and proteomics; (iv) epigenetic mapping using CUT&RUN and ATAC-seq to assess chromatin accessibility and BET protein occupancy. In parallel, primary and immortalized proximal tubular epithelial cells were used to model HFpEF-associated renal stress using metabolic (palmitate) and inflammatory (IL-1β) stimuli, together with a paracrine cardiomyocyte co-culture system to recapitulate in vivo signatures and cardio-renal communication. Results HFpEF mice exhibited significantly reduced renal clearance compared with controls, indicating impaired kidney function. Histological analyses revealed renal injury characterized by tubular damage, glomerular hypertrophy, and increased interstitial fibrosis (Fig. 1 left). Integrated transcriptomic and proteomic profiling demonstrated activation of pro-inflammatory (NF-κB, cytokine signaling) and pro-fibrotic (TGF-β/SMAD) pathways, alongside suppression of metabolic and mitochondrial programs, particularly fatty acid oxidation and peroxisomal function (Fig. 1 right). Chromatin profiling revealed increased BRD2 and BRD4 occupancy at regulatory regions of transcription start sites, accompanied by enhanced chromatin accessibility, establishing a direct epigenetic link between cardiometabolic stress and renal remodeling (Fig. 2). These dysregulated pathways were recapitulated in vitro, where proximal tubular stress induced maladaptive transcriptional programs, lipotoxic responses, and paracrine signaling in cardiorenal co-culture systems, validating the in vivo findings. Conclusions HFpEF-related renal dysfunction is a lifestyle-driven, epigenetically programmed injury rather than solely a consequence of ageing or hemodynamic stress. BET-dependent chromatin remodeling drives key metabolic and inflammatory pathways, with proximal tubules as major effectors. These findings identify BET signaling as a promising therapeutic target to preserve renal function in HFpEF.