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

Chien-Ling Lee, Jianxiu Zhang and Liang Feng ()
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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

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62714-w

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