IL-17A Mediates Cardiac Hypertrophy in Chronic Kidney Disease through the IL-23/Th17 Axis
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Background
Chronic kidney disease (CKD) is a major risk factor for cardiovascular morbidity, promoting left ventricular hypertrophy (LVH) prior to overt heart failure. The mechanisms underlying early cardiac remodeling in CKD remain incompletely understood. The IL-23/Th17/IL-17A inflammatory axis has emerged as a key mediator of cardiovascular pathology; however, its role in CKD-associated cardiac remodeling remains unclear. This study aimed to elucidate the contribution of this pathway to the early cardiac changes in CKD.
Methods
Using a 5/6 nephrectomy (5/6Nx) mouse model of CKD, we evaluated cardiac structure, mitochondrial function, and inflammatory signaling. Cardiomyocyte transcriptomes were analyzed by RamDA-seq to identify molecular alterations. Circulating cytokines were profiled longitudinally, and IL-17A neutralization experiments were performed to assess causality. In addition, serum IL-12p40 concentrations were measured in patients with CKD and correlated with their renal function and cardiac remodeling indices.
Results
At 16 weeks post-5/6Nx, mice developed LVH with preserved systolic function, accompanied by increased oxidative stress and mitochondrial structural abnormalities, but without significant myocardial fibrosis. Transcriptomic analysis identified oxidative phosphorylation as the most significantly downregulated pathway in cardiomyocytes. Despite increased mitochondrial DNA copy number and elevated PGC-1α expression, ATP production and mitochondrial respiratory chain proteins were reduced, indicating mitochondrial dysfunction. Circulating IL-12p40 and IL-23 levels increased progressively, concurrent with expansion of splenic Th17 cells and elevated cardiac IL-17A expression. Recombinant IL-17A directly impaired mitochondrial respiration in cultured cardiomyocytes. In vivo, IL-17A neutralization attenuated LVH, reduced oxidative stress, and partially restored mitochondrial protein expression without improving renal function. In patients with CKD, serum IL-12p40 levels correlated inversely with estimated glomerular filtration rate and positively with left ventricular mass index, supporting clinical relevance.
Conclusions
Activation of the systemic IL-23/Th17/IL-17A axis contributes to early CKD-associated cardiac remodeling by promoting oxidative stress and mitochondrial dysfunction. Circulating IL-12p40 may serve as a biomarker of cardiorenal remodeling, and the IL-23/IL-17A pathway represents a potential therapeutic target.
CLINICAL PERSPECTIVE
What Is New?
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In a mouse model of chronic kidney disease (CKD), activation of the systemic IL-23/Th17/IL-17A axis was associated with left ventricular hypertrophy, oxidative stress, and mitochondrial dysfunction before the development of overt systolic dysfunction or myocardial fibrosis.
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In patients with CKD, circulating IL-12p40 levels were associated with both renal dysfunction and increased left ventricular mass.
What Are the Clinical Implications?
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These findings identify the IL-23/Th17/IL-17A axis as a potential mechanistic link between CKD and early cardiac remodeling, suggesting that inflammation may contribute to cardiac injury independently of worsening renal function.
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Targeting the IL-23/IL-17A pathway may represent a potential therapeutic strategy to prevent or attenuate CKD-associated cardiac remodeling before the development of overt heart failure.
