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CerS6 links ceramide metabolism to innate immune responses in diabetic kidney disease

Author

Listed:
  • Zijing Zhu

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Yun Cao

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Yonghong Jian

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Hongtu Hu

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Qian Yang

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Yiqun Hao

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Houhui Jiang

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Zilv Luo

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Xueyan Yang

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Weiwei Li

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Jijia Hu

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Hongyan Liu

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Wei Liang

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Guohua Ding

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

  • Zhaowei Chen

    (Renmin Hospital of Wuhan University
    Nephrology and Urology Research Institute of Wuhan University
    Hubei Clinical Research Center of Kidney Disease)

Abstract

Ectopic lipid deposition, mitochondrial injury, and inflammatory responses contribute to the development of diabetic kidney disease (DKD); however, the mechanistic link between these processes remains unclear. In this study, we demonstrate that the ceramide synthase 6 (CerS6) is primarily localized in podocytes of the glomeruli and is upregulated in two different models of diabetic mice. Podocyte-specific CerS6 knockout ameliorates glomerular injury and inflammatory responses in male diabetic mice and in male mice with adriamycin-induced nephropathy. In contrast, podocyte-specific overexpression of CerS6 sufficiently induces proteinuria. Mechanistically, CerS6-derived ceramide (d18:1/16:0) can bind to the mitochondrial channel protein VDAC1 at Glu59 residue, initiating mitochondrial DNA (mtDNA) leakage, activating the cGAS-STING signaling pathway, and ultimately promoting an immune-inflammatory response in the kidney. Importantly, CERS6 expression is increased in podocytes from kidney biopsies of patients with DKD and focal segmental glomerulosclerosis (FSGS), and the expression level of CERS6 is correlated negatively with glomerular filtration rate and positively with proteinuria. Thus, our findings suggest that targeting CerS6 may be a potential therapeutic strategy for proteinuric kidney diseases.

Suggested Citation

  • Zijing Zhu & Yun Cao & Yonghong Jian & Hongtu Hu & Qian Yang & Yiqun Hao & Houhui Jiang & Zilv Luo & Xueyan Yang & Weiwei Li & Jijia Hu & Hongyan Liu & Wei Liang & Guohua Ding & Zhaowei Chen, 2025. "CerS6 links ceramide metabolism to innate immune responses in diabetic kidney disease," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-56891-x
    DOI: 10.1038/s41467-025-56891-x
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    References listed on IDEAS

    as
    1. Parker C. Wilson & Yoshiharu Muto & Haojia Wu & Anil Karihaloo & Sushrut S. Waikar & Benjamin D. Humphreys, 2022. "Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    2. A. Mitrofanova & S. K. Mallela & G. M. Ducasa & T. H. Yoo & E. Rosenfeld-Gur & I. D. Zelnik & J. Molina & J. Varona Santos & M. Ge & A. Sloan & J. J. Kim & C. Pedigo & J. Bryn & I. Volosenco & C. Faul, 2019. "SMPDL3b modulates insulin receptor signaling in diabetic kidney disease," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    3. Philipp Hammerschmidt & Sophie M. Steculorum & Cécile L. Bandet & Almudena Río-Martín & Lukas Steuernagel & Vivien Kohlhaas & Marvin Feldmann & Luis Varela & Adam Majcher & Marta Quatorze Correia & Rh, 2023. "CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    4. Shashank Dadsena & Svenja Bockelmann & John G. M. Mina & Dina G. Hassan & Sergei Korneev & Guilherme Razzera & Helene Jahn & Patrick Niekamp & Dagmar Müller & Markus Schneider & Fikadu G. Tafesse & Si, 2019. "Ceramides bind VDAC2 to trigger mitochondrial apoptosis," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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