Combination of genetic studies and animal modeling proposes TMPRSS9 as a candidate gene for serum K⁺ variations

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.