Sex-Dependency of T Cell-Induced Salt-Sensitive Hypertension and Kidney Damage

It is established that the immune system, namely T cells, plays a role in the development of hypertension and renal damage in male Dahl salt-sensitive (SS) rats, but far less is known about this relationship in females. Rats with genetically deleted T cells via CD247 gene mutation on the Dahl SS background (SS^CD247-/-) were utilized to interrogate the effect of sex and T cells on salt sensitivity.

We assessed the hypertensive and kidney injury phenotypes in male versus female SS and SS^CD247-/- rats challenged with 3 weeks of high salt (4.0% NaCl). Differences in T cell activation genes were examined in renal T cells from male and female SS rats, and a sex-specific adoptive transfer was performed by injecting male or female splenocytes into either male or female SS^CD247-/- recipients to determine the potential contribution of T cell sex.

The lack of functional T cells in SS^CD247-/- rats significantly reduced salt-induced hypertension and proteinuria in both sexes, although SS^CD247-/- females exhibited greater protection from kidney damage. Adoptive transfer of either Dahl SS male or female splenocytes into SS^CD247-/- male recipients exacerbated hypertension and proteinuria compared with controls, while in SS^CD247-/- female recipients, exacerbation of disease occurred only upon transfer of male, but not female, SS splenocytes.

The absence of T cells in the SS^CD247-/- normalized sex differences in blood pressure, though sex differences in renal damage persisted. Splenocyte transfer experiments demonstrated that salt sensitivity is amplified if the sex of the T cell or the recipient is male.