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PHLDA1 is a shared diagnostic mediator for inflammatory fibrosis in heart and kidney

ABSTRACT: Background: Inflammation-driven fibrosis represents a common pathological endpoint in both heart failure (HF) and chronic kidney disease (CKD), which together affect over 1 billion people worldwide. Understanding the shared molecular mechanisms by which inflammation contributes to the pathogenesis of HF and CKD is crucial for enabling early diagnosis and guiding the development of broad-spectrum therapeutic strategies. Methods: Utilizing multi-omics technologies and machine learning algorithms, we performed an integrative analysis of HF and chronic kidney disease CKD samples to uncover shared mechanisms underlying inflammation-induced fibrosis. Furthermore, key regulators identified through bioinformatic analysis were experimentally validated using primary cell co-culture assays, gene knockout approaches, and bulk RNA sequencing. Results: Single-nucleus RNA sequencing (snRNA-seq) revealed concurrent upregulation of IL-1β and Pleckstrin Homology-Like Domain Family A Member 1 (PHLDA1) in both cardiac M1 macrophages and injured proximal tubular epithelial (PTE) cells. PHLDA1 promotes IL-1β expression and knockout of PHLDA1 suppressed NF-κB signaling and renal fibrosis. Administration of IL-1β induced PHLDA1 expression in cardiac fibroblasts and renal PDGFRβ⁺ cells, suggesting a positive feedback loop that contributes to fibrosis. Conclusions: In this study, we identified PHLDA1 as a key driver of fibrosis in both the heart and kidney, acting through IL-1β mediated intercellular crosstalk. These findings highlight PHLDA1 as a promising therapeutic target for mitigating fibrosis in cardio-renal syndrome.

ORGANISM(S): Homo sapiens

PROVIDER: GSE313814 | GEO | 2026/02/25

REPOSITORIES: GEO

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Project description:Background: Cardiovascular disease (CVD) causes more than 50% of deaths in patients with advanced chronic kidney disease (CKD). CVD degree correlates with CKD severity. Clinical studies suggest that kidney-derived factors contribute to the development of CVD in CKD, independently of co-morbidities like hypertension and hyperglycemia. However, to date, no kidney-specific humoral risk factor that triggers direct cardiotoxicity has yet been identified, primarily due to the paucity of studies in patients with reno-cardiac disease. Here, we investigate how, in CKD patients, circulating extracellular vesicles (EVs) facilitate pathological kidney-heart communication, thereby causing cardiotoxicity, impairing cardiac function and contributing to heart failure (HF) progression. Methods and results: EVs isolated from the plasma of patients with CKD (hCKD-EVs), but not healthy controls (hCtr-EVs), were cardiotoxic, significantly inducing apoptosis both in vitro and in vivo and impairing contractility of isolated adult rat primary CMs in vitro. Likewise, EVs isolated from both plasma and kidneys of adenine diet-induced CKD mice were also cardiotoxic. Pharmacologically depleting circulating EVs in CKD mice significantly recovered cardiac function and ameliorated HF, suggesting CKD-EVs play a causal role in HF pathogenesis. Small RNA sequencing and q-RT-PCR validation uncovered distinct miRNAs enriched in both human and mouse CKD-EVs, compared to Ctr-EVs. CKD-EV-miRNA mimics were cardiotoxic to human ventricular AC16 myocytes inducing apoptosis and to iPSC-derived cardiomyocytes, impairing contractility and downregulating contractile gene expression. Interestingly, levels of endogenous primary miRNAs corresponding to CKD-EV-miRNAs were significantly higher in CKD-kidney tissues, specifically in CD45-veCD31-ve renal cells, but not in CKD-livers, CKD-lungs or CKD-PBMCs from peripheral blood, a result that suggests that CKD-EV-miRNAs originate renally. Remarkably, CKD-EV-miRNA levels correlated with established markers of cardiac injury, uncovering the presence of sub-clinical heart disease and demonstrating heterogeneity in CKD patients not yet diagnosed with HF. Conclusion: Collectively, our human subject and mouse studies show that circulating CKD-EVs, carrying distinct renal-derived miRNAs, mediate the molecular crosstalk that contributes to the pathogenesis of HF in CKD. Consequently, CKD-EVs hold promise as diagnostic and prognostic biomarkers for early disease detection and as targets for novel therapeutic interventions in chronic reno-cardiac disease.

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PHLDA1 is a shared diagnostic mediator for inflammatory fibrosis in heart and kidney

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