Chronic Stress Induces Sex-Specific Renal Mitochondrial Dysfunction in Mice

Chronic psychological stress has been linked to renal disease and is also associated with the development of hypertension. However, the mechanisms by which chronic stress alters renal function and promotes hypertension is unclear. This study tested the hypothesis that chronic stress causes impaired renal mitochondrial function that can lead to increased arterial pressure. Adult male and female C57BL/6 mice were exposed to a chronic unpredictable stress (CUS), or non-stress control, protocol for 28 consecutive days. The protocol models mild, persistent, and variable stress that is a common occurrence in daily life. The CUS protocol induced anxiety relevant behaviors in both male and female mice. CUS increased blood pressure in both sexes, but the increase was greater in female mice. Renal mitochondrial function was unchanged by CUS in male mice. In contrast, renal mitochondrial function was impaired in the proestrus phase of the estrous cycle in female mice. Female mice exposed to CUS had low renal progesterone. Impaired mitochondrial function correlated with low renal progesterone, which correlated with increased blood pressure. Renal sex steroids were unchanged by CUS in males. Urinary albumin excretion was significantly increased in female mice exposed to CUS. CUS did not affect urinary albumin excretion in male mice exposed to CUS. These data show a direct role for CUS in causing an increase in blood pressure. The mechanisms causing increased pressure in CUS-exposed mice are sex-dependent, with low renal progesterone leading to impaired renal mitochondrial function as a potential mechanism underlying the elevated pressure in female mice.