Sex differences in renal acid-base regulation

Transport across cells of the renal tubule differs between females and males, possibly as a consequence of varying abundance of transport proteins along the nephron. We hypothesized that sex-specific differences in the physiological responses and in transport protein abundances exist in the context of acid-base challenges. We used female and male C57Bl/6J mice and challenged them with acid (NH₄Cl) or base (NaHCO₃) in their drinking water for 8 days. Blood and urine samples were collected at baseline and at the end of the experimental period before kidneys were harvested and protein abundances determined. In response to NH₄Cl challenge, the significant decreases in urine pH, blood HCO₃^-, and base excess were similar in both sexes despite a smaller intake of NH₄Cl in male compared with female mice. In response to NaHCO₃ challenge, urine pH significantly increased in both sexes; however, blood pH, HCO₃^-, and base excess were increased significantly and to a greater extent in male compared with female mice. Two-way analysis of variance demonstrated that out of the 12 tested proteins, 7 were significantly affected by sex, 7 were significantly affected by treatment, and the interaction of sex and treatment was significant for Na⁺/K⁺/2Cl^- cotransporter, NKCC2. In summary, our study demonstrates 1) sex differences in protein abundance, 2) proteins are affected differentially in response to acid-base challenges, and 3) NKCC2 is a new and potentially important player in acid-base regulation.NEW & NOTEWORTHY Disturbances in acid-base regulation are common and can have detrimental effects. Here, we provide evidence that acid-base disturbances in males and females are consistent with female mice being able to defend acid and base challenges more effectively. Our data have potential clinical importance in humans regarding the treatment of acidosis and alkalosis in males versus females.