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Abstract: PO2447

Targeting Innate Immune-Polyamine Axis Prevents CKD-Associated Cardiac Hypertrophy

Session Information

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Yang, Ke, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
  • Han, Wenhao, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
  • Zhu, Yingguo, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China
  • Zhao, Jinghong, Xinqiao Hospital, Army Medical University (Third Military Medical University), Chongqing, China

Group or Team Name

  • Department of Nephrology, the Key Laboratory for the Prevention and Treatment of Chronic Kidney Disease of Chongqing, Chongqing Clinical Research Center of Kidney and Urology Diseases, Xinqiao Hospital, Army Medical University (Third Military Medical University)
Background

It is well recognized in clinic that patients with chronic kidney disease (CKD) have a higher risk for developing cardiovascular diseases including cardiac hypertrophy. However, the pathogenetic mechanisms remain poorly understood.

Methods

The hypertrophic phenotype changes and metabolic characteristics of neonatal rat cardiomyocytes were studied after incubated with serum from 5 stage CKD patients, as well as myocardium from mice with or without CKD, accompanied by bulk RNA-seq analysis. The role and mechanism of CKD in inducing cardiac hypertrophy were evaluated in vivo and ex vivo, and confirming in targeted gene knockout and cardiomyocyte-specific knockout mice.

Results

Here, we show that adult cardiomyocytes are characterized by restrained polyamine metabolism, while CKD activates polyamine metabolism especially ornithine decarboxylase (ODC1)-putrescine metabolic axis in cardiomyocytes. Then, we reveal that nuclear factor kappa B (NFκB) in cardiomyocytes not only drives hypertrophic program under CKD milieu, but also conservatively dominates the transcriptional activation of ODC1-putrescine metabolic axis. Meanwhile, activation of ODC1-putrescine metabolic axis in cardiomyocytes acts as a prerequisite for the efficient initiation of NFκB-driven hypertrophic program, rather than a pathogenic factor for cardiac hypertrophy. Furthermore, mitochondrial oxidative damage is a prominent feature of cardiomyocytes under CKD milieu. The damaged mitochondria release mitochondrial DNA into the cytosol and stimulates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in cardiomyocytes, which subsequently activates NFκB. Therefore, myocardial cGAS-STING-NFκB pathway plays a critical role in CKD-associated cardiac hypertrophy through immune surveillance of mitochondrial fitness as well as integrating hypertrophic program and polyamine metabolism.

Conclusion

Our study uncovers a previously unrecognized role of innate immune-polyamine axis in CKD-associated cardiac hypertrophy. Targeting innate immune-polyamine axis may represent a promising strategy to prevent and treat CKD-associated cardiac hypertrophy.

Funding

  • Government Support – Non-U.S.