Humanized Diets Define Optimal Pressure-Lowering Response to Dietary Potassium in Mice

Le résumé fourni par la source

Background: High-potassium (K) diets lower blood pressure (BP) in rodents and humans but can also raise BP when consumed in excessive amounts. We reported (JCI Insight, 2023) the K-mediated BP lowering response, driven by the inactivation of the thiazide-sensitive sodium chloride cotransporter (NCC), is offset by an increase in Epithelial Sodium Channel (ENaC) and tubule injury responses when an extremely high K diet is chronically consumed. Here, we define the optimal dietary K level that inactivates NCC without activating ENaC and injury responses. Methods: Male mice (C57Bl6J) were fed high-sodium diets containing six different K contents, comparing the control diet (1% K) with traditional extremes (0.1% and 5% K) and those that mimic a range of K levels found in human diets (0.35%, 0.7%, and 1.7%). NCC- (hydrochlorothiazide-sensitive) and ENaC- (benzamil-sensitive) dependent sodium handling was assessed in clearance studies. BP was measured by telemetry. Single-nucleus RNA sequencing (snRNA-Seq) characterized the transcriptomic responses to the K diets. NCC and ENaC Protein abundance and post-translational activation were evaluated by Western Blot and immunofluorescence microscopy. Results: Systolic blood pressure during the active period exhibits a ‘U-shaped’ relationship with dietary K, with the lowest blood pressure at 1.7% K. As potassium is reduced from 1.7% (0.1%, 0.35%, and 0.7% K groups), BP, NCC phosphorylation, and thiazide sensitivity increase; however, they become benzamil-sensitive in the 5% K group, as ENaC cleavage increases. Aldosterone levels increase with increasing dietary K, but are significantly lower in the 0.1%, 0.35%, and 0.7% groups compared to the control group. snRNA-seq revealed that the transcriptomes of the proximal tubule and CNT were most significantly altered by K+ diets, with distinct changes for each K diet and cell type, illuminating new pathways enriched in ion transport and morphogenetic processes that may contribute to the effects of K on BP. Conclusion: An optimal dietary K level (1.7%) that maximally reduces BP in mice by suppressing NCC activity, limiting aldosterone activation of ENaC, and regulating transport and tubule remodeling pathways in the proximal tubule and CNT was defined. This diet mimics the human DASH diet in K content and further supports its efficacy as a BP-lowering tool. Funding: NIDDK Support

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.