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Multimodal single cell sequencing implicates chromatin accessibility and genetic background in diabetic kidney disease progression

Author

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  • Parker C. Wilson

    (Washington University in St. Louis)

  • Yoshiharu Muto

    (Washington University in St. Louis)

  • Haojia Wu

    (Washington University in St. Louis)

  • Anil Karihaloo

    (Novo Nordisk Research Center Seattle Inc)

  • Sushrut S. Waikar

    (Boston University School of Medicine, Boston Medical Center)

  • Benjamin D. Humphreys

    (Washington University in St. Louis
    Washington University in St. Louis)

Abstract

The proximal tubule is a key regulator of kidney function and glucose metabolism. Diabetic kidney disease leads to proximal tubule injury and changes in chromatin accessibility that modify the activity of transcription factors involved in glucose metabolism and inflammation. Here we use single nucleus RNA and ATAC sequencing to show that diabetic kidney disease leads to reduced accessibility of glucocorticoid receptor binding sites and an injury-associated expression signature in the proximal tubule. We hypothesize that chromatin accessibility is regulated by genetic background and closely-intertwined with metabolic memory, which pre-programs the proximal tubule to respond differently to external stimuli. Glucocorticoid excess has long been known to increase risk for type 2 diabetes, which raises the possibility that glucocorticoid receptor inhibition may mitigate the adverse metabolic effects of diabetic kidney disease.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32972-z
    DOI: 10.1038/s41467-022-32972-z
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    Cited by:

    1. Haojia Wu & Eryn E. Dixon & Qiao Xuanyuan & Juanru Guo & Yasuhiro Yoshimura & Chitnis Debashish & Anezka Niesnerova & Hao Xu & Morgane Rouault & Benjamin D. Humphreys, 2024. "High resolution spatial profiling of kidney injury and repair using RNA hybridization-based in situ sequencing," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Wei E. Gordon & Seungbyn Baek & Hai P. Nguyen & Yien-Ming Kuo & Rachael Bradley & Sarah L. Fong & Nayeon Kim & Alex Galazyuk & Insuk Lee & Melissa R. Ingala & Nancy B. Simmons & Tony Schountz & Lisa N, 2024. "Integrative single-cell characterization of a frugivorous and an insectivorous bat kidney and pancreas," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    3. Nicolas Ledru & Parker C. Wilson & Yoshiharu Muto & Yasuhiro Yoshimura & Haojia Wu & Dian Li & Amish Asthana & Stefan G. Tullius & Sushrut S. Waikar & Giuseppe Orlando & Benjamin D. Humphreys, 2024. "Predicting proximal tubule failed repair drivers through regularized regression analysis of single cell multiomic sequencing," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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