Auberson Muriel, Wang Dongmei, Ehret Elodie, Corre Tanguy, Anand Deepika, Mechakra Asma, Staub Olivier, Bochud Murielle, Hummler Edith
Department of Biomedical Sciences, University of Lausanne, 27 rue du Bugnon, 1011, Lausanne, Switzerland.
Department of Epidemiology and Health Systems (DESS), University Center for General Medicine and Public Health (UNISANTE), Lausanne, Switzerland.
Sci Rep. 2025 Jul 12;15(1):25211. doi: 10.1038/s41598-025-11106-7.
A candidate gene association analysis identified TMPRSS9 as gene for potassium sensitivity in women. To validate this finding, constitutive and conditional Tmprss9 knockout mice were generated and subjected to dietary K deprivation and K loading. Interestingly, mouse renal Tmprss9 gene expression was similar in both sexes on standard diet but differed when challenged with K-deprivation or -loading in wildtype (WT) mice. Constitutive deficiency of Tmprss9 was evidenced on a transcriptional level in knockout (KO) mice. Serum Na levels were lower in male and female KO mice on low K (LKD), while on high K (HKD) diet, serum K only increased in male KO mice. Upon all diet conditions namely standard diet (SD), LKD and HKD the protein abundances of sodium transporting proteins like the sodium-chloride symporter (NCC), alpha and gamma epithelial sodium channel (ENaC) subunits as well as their ratio of cleaved/full length protein and the sodium-hydrogen exchanger 3 (NHE3) were similar in WT and KO mice and/or showed only minor differences. We propose that in human, TMPRSS9 may function as a sex-specific modifier gene for serum K handling in women, whereas in mice, male rather than female Tmprss9 KO retained serum K on HKD.
一项候选基因关联分析确定TMPRSS9为女性钾敏感性的相关基因。为验证这一发现，构建了组成型和条件型Tmprss9基因敲除小鼠，并使其接受饮食钾缺乏和钾负荷实验。有趣的是，在标准饮食条件下，小鼠肾脏Tmprss9基因表达在两性中相似，但在野生型（WT）小鼠受到钾缺乏或钾负荷挑战时则有所不同。在基因敲除（KO）小鼠中，转录水平上证实了Tmprss9的组成型缺陷。低钾饮食（LKD）条件下，雄性和雌性KO小鼠的血清钠水平较低，而在高钾饮食（HKD）条件下，只有雄性KO小鼠的血清钾升高。在所有饮食条件下，即标准饮食（SD）、LKD和HKD，野生型和基因敲除小鼠中钠转运蛋白如氯化钠协同转运蛋白（NCC）、α和γ上皮钠通道（ENaC）亚基的蛋白质丰度，以及它们的裂解/全长蛋白比例和钠氢交换体3（NHE3）相似，和/或仅显示出微小差异。我们提出，在人类中，TMPRSS9可能作为女性血清钾处理的性别特异性修饰基因，而在小鼠中，雄性而非雌性Tmprss9基因敲除小鼠在高钾饮食时能保留血清钾。
