STAT1 modulated myeloid responses determine cardiac dysfunction post chronic kidney injury

Background Signal Transducer and Activator of Transcription-1 (STAT1) pathway serves as a central hub coordinating immune-metabolic communication and cardiac remodeling. We reanalyzed publicly available human myocardial proteomic data from a recent study by Jani et al.(1) which showed significant downregulation of STAT1 in proteomic analysis of human myocardium from diabetic kidney disease patients versus healthy controls which was consistent with our findings in a swine chronic kidney disease (CKD) model with similarly reduced cardiac STAT1 expression (Fig. 1A,B). Objectives To investigate the impact on structural, functional, and immunological cardiac remodeling of STAT1 signaling CKD induced cardiac dysfunction. Methods Chronic kidney disease (CKD) was induced by 30 minutes of unilateral ischemia reperfusion (IRI) of the left kidney in 8 week-old transgenic STAT1 knockout (STAT1−/−) and wild-type (WT) mice. Echocardiography was performed to assess parameters such as E/A ratio. Bulk RNA sequencing was performed on left ventricular (LV) myocardium and flow cytometry was conducted on whole blood and LV tissue to quantify immune cells. All analyses were performed with sex-stratified evaluation to identify potential sex-specific effects Results Bulk RNA sequencing of LV at 30 days after renal IRI revealed alterations in the JAK–STAT pathway in WT mice versus sham (Fig. 1C), highlighting a critical role of STAT1 in post-injury cardiac remodeling. Renal IRI induced atrophy of the left kidney and an initial reduction in heart weight that partially recovered by 90 days (Fig. 2A–C). Echocardiography showed that kidney injury led to a reduced E/A ratio in WT mice at 30 days (Fig. 2B), an effect absent in Stat1⁻/⁻ mice (Fig. 2D,E).Systemic immune profiling revealed elevated circulating Ly6C^int monocytes and reduced neutrophils in Stat1⁻/⁻ mice versus WT sham (Fig. 2F,G), with Ly6C^int monocytes remaining higher at 30 days in Stat1⁻/⁻ than in WT. Cardiac FACS at 90 days post-IRI showed pronounced immune cell expansion in Stat1⁻/⁻ hearts; macrophages (CD11b⁺F4/80⁺), tissue-resident macrophages (F4/80⁺CD64⁺), and patrolling Ly6C⁻ monocytes were significantly elevated in Stat1⁻/⁻ versus sham (Fig. 2H–L). These changes were predominantly observed in males, whereas females showed attenuated responses, underscoring sex-dependent immune and remodeling outcomes. Conclusions STAT1-dependent immune dysregulation after renal IRI shapes remote cardiac remodeling. Elevated circulating Ly6C^int monocytes and reduced neutrophils at baseline in Stat1⁻/⁻ mice are associated with a later expansion of reparative cardiac myeloid subsets at 90 days and preserved diastolic function. In contrast, WT mice develop more pronounced diastolic dysfunction despite comparable renal atrophy, particularly in males, indicating that STAT1-modulated systemic immune priming drives divergent cardiac outcomes along the kidney–heart axis.