Key result
STAT1 inhibition reduces myocardial contractile performance by ~20% and induces diastolic dysfunction.
Why the study?
Does STAT1 signaling mediate cardiac dysfunction and inflammatory responses in chronic kidney disease?
Does STAT1 signaling mediate cardiac dysfunction and inflammatory responses in chronic kidney disease?
Loss of STAT1 alters the cardiac inflammatory transcriptome and is associated with early diastolic dysfunction in a murine model of chronic kidney disease, highlighting its complex role in cardiorenal syndrome.
Background Clinical trials show that individuals with chronic kidney disease (CKD), have a higher risk of heart failure (HF). In our swine model of CKD (renal microembolization), proteomic analysis of left ventricular tissue revealed STAT1 dysregulation in CKD compared to control (WT) swine. STAT1 functions as a central inflammatory mediator activated by type I interferons and various pro-inflammatory cytokines, which are elevated in CKD as a consequence of kidney injury. Once activated, STAT1 drives the expression of genes involved in inflammatory and immune responses[1][2], and may thereby play a central role in HF development in CKD. Purpose To investigate the impact of STAT1 signaling CKD induced cardiac dysfunction. Methods CKD was induced by ischemia-reperfusion injury of the left Kidney at the age of 8 to 11 weeks in Transgenic Stat1 Knockout (Stat1-/-) mice and WT Mice. After 1 and 3 months, cardiac ultrasound was performed and left ventricle (LV) and kidney tissue were processed for histology (Picrosirius Red staining), while Bulk RNA transcriptomic analysis was performed in LV myocardium. In addition, the effect of STAT1 inhibition (Fludarbine) on contractile performance was assessed in cultured human myocardial slices. Results Renal Ischemia reperfusion injury induced chronic kidney disease (CKD) characterized by pronounced renal fibrosis compared to the contralateral kidney, as visualized by Picrosirius Red staining, that was not different between WT and Stat1-/- mice (A, B). Echocardiographic analysis revealed diastolic dysfunction as evidenced by a trend toward increased E’/A‘ ratio (E) and prolonged isovolumetric relaxation time (IVRT) (F) in Stat1-/- mice. RNA sequencing of cardiac tissue identified CKD-induced alterations in multiple signaling pathways, incl the JAK-STAT pathway in WT but not Stat1-/- mice (C). Conversely, Stat1-/- mice, CKD induced a distinct immunological and inflammatory gene expression profile in the heart (D). In human living myocardial slices, STAT1 inhibition with Fludarabine resulted in significant downregulation (around 20%) of contractile performance. Conclusions Our results emphasize a pivotal role of STAT1 in mediating cardiac responses to chronic kidney disease. Loss of STAT1 profoundly alters the cardiac inflammatory transcriptome and is associated with early diastolic dysfunction and increased macrophage infiltration. These findings position STAT1 axis as a potential therapeutic target in cardiorenal syndrome. Future studies using advanced imaging techniques and functional analysis with the living myocardial slices can further elucidate the underlying mechanisms and support clinical translation.
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D'ambrosio et al. (2026) studied Chronic kidney disease induced cardiac dysfunction. STAT1 knockout and STAT1 inhibition (Fludarabine) vs. Wild-type (WT) mice and untreated control was evaluated on Cardiac diastolic function and contractile performance. STAT1 knockout in mice with chronic kidney disease induced early diastolic dysfunction, and STAT1 inhibition in human myocardial slices reduced contractile performance by approximately 20%.
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