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Molecular mechanisms of thiazide-like diuretics-mediated inhibition of the human Na-Cl cotransporter

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  • Chien-Ling Lee

    (Stanford University School of Medicine)

  • Jianxiu Zhang

    (Stanford University School of Medicine)

  • Liang Feng

    (Stanford University School of Medicine)

Abstract

Thiazide-type and thiazide-like diuretics are structurally distinct first-line antihypertensive drugs that target the sodium-chloride cotransporter (NCC) in the kidney. Thiazide-like diuretics are reported to have better cardioprotective effects than thiazide-type diuretics, but whether this is due to differences in NCC-inhibition mechanisms, if there is any, remains unclear. To understand the molecular mechanisms of NCC inhibition by thiazide-like diuretics, we determine the structures of human NCC (hNCC) bound to two of the most widely used thiazide-like diuretics, chlorthalidone and indapamide, using cryogenic electron microscopy (cryo-EM). Structural analyses reveal shared features and distinctions between NCC-inhibition by thiazide-like and thiazide-type diuretics. Furthermore, structural comparisons allow us to identify polymorphisms in hNCC that have substantial differential effects on the potencies of specific thiazide-like and thiazide-type diuretics. Our work provides important insights into the molecular pharmacology of NCC and a blueprint for developing precision medicine to manage hypertension with thiazide-like and thiazide-type diuretics.

Suggested Citation

  • Chien-Ling Lee & Jianxiu Zhang & Liang Feng, 2025. "Molecular mechanisms of thiazide-like diuretics-mediated inhibition of the human Na-Cl cotransporter," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-62714-w
    DOI: 10.1038/s41467-025-62714-w
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    References listed on IDEAS

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    1. Minrui Fan & Jianxiu Zhang & Chien-Ling Lee & Jinru Zhang & Liang Feng, 2023. "Structure and thiazide inhibition mechanism of the human Na–Cl cotransporter," Nature, Nature, vol. 614(7949), pages 788-793, February.
    2. Yongxiang Zhao & Heidi Schubert & Alan Blakely & Biff Forbush & Micholas Dean Smith & Jesse Rinehart & Erhu Cao, 2024. "Structural bases for Na+-Cl− cotransporter inhibition by thiazide diuretic drugs and activation by kinases," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Genevieve L. Wojcik & Mariaelisa Graff & Katherine K. Nishimura & Ran Tao & Jeffrey Haessler & Christopher R. Gignoux & Heather M. Highland & Yesha M. Patel & Elena P. Sorokin & Christy L. Avery & Gil, 2019. "Genetic analyses of diverse populations improves discovery for complex traits," Nature, Nature, vol. 570(7762), pages 514-518, June.
    4. Yongxiang Zhao & Kasturi Roy & Pietro Vidossich & Laura Cancedda & Marco De Vivo & Biff Forbush & Erhu Cao, 2022. "Structural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
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