Integrated multi-omics reveals epigenetic control of renal damage in HFpEF
N Atzemian, S Mohammed, L Di Venanzio, E Gorica, H Kaipananickal, J Okabe, P Pokreisz, S Maxwell, S Costantino, A Kiss, F Ruschitzka, A El-Osta, F PaneniAbstract
Introduction
Heart failure with preserved ejection fraction (HFpEF) represents a major and growing global health burden driven by ageing, obesity, and cardiometabolic comorbidities. Lifestyle and environmental exposures are central to HFpEF pathogenesis and are known to exert their long-term effects through epigenetic mechanisms. However, how epigenetic regulation contributes to renal dysfunction, a key determinant of outcome in HFpEF, remains largely unexplored.
Methods
A well-established two-hit mouse model of cmHFpEF 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 normal diet (10 kcal% fat) and vehicle. Renal phenotyping included: (i) functional assessment via plasma creatinine, cystatin C, and galectin-3; (ii) structural analysis by H&E, Masson’s Trichrome and PAS staining; (iii) molecular profiling by RNA-seq and proteomics; and (iv) epigenetic mapping using CUT&RUN to define chromatin accessibility and BET protein occupancy.
Results
HFpEF mice exhibited a significant and progressive reduction in transdermal GFR compared with controls, indicating early renal functional impairment. This was accompanied by increased plasma levels of renal dysfunction markers, including cystatin C and creatinine, alongside elevated inflammatory mediators. Histological analyses revealed marked kidney injury characterised by tubular damage, glomerular hypertrophy, increased interstitial fibrosis, and evidence of endothelial disruption (Figure 1A). Integrated transcriptomic and proteomic profiling of renal tissue demonstrated coordinated activation of pro-inflammatory (NF-κB, cytokine signalling), pro-fibrotic (TGF-β/SMAD, extracellular matrix organisation), and oxidative stress pathways, together with suppression of metabolic and mitochondrial programmes, including fatty acid oxidation and peroxisome-related pathways (Figure 1B). Chromatin profiling identified increased BRD2- and BRD4-associated occupancy at regulatory regions of genes governing inflammation, fibrosis, and metabolic regulation, providing a direct epigenetic link between cardiometabolic stress and maladaptive renal remodelling (Figure 2).
Conclusions
HFpEF-associated renal dysfunction represents a lifestyle-driven, epigenetically programmed form of kidney injury rather than an inevitable consequence of ageing or haemodynamic stress. By integrating functional, structural, and multi-omic profiling, we identify bromodomain-dependent regulatory networks as central drivers of renal damage, providing a mechanistic bridge between cardiometabolic risk and kidney failure. These findings support epigenetic modulation as a clinically translatable strategy to preserve renal function and improve outcomes in patients with HFpEF.For image description, please refer to the figure legend and surrounding text.For image description, please refer to the figure legend and surrounding text.