Sex differences in renal transporters: assessment and functional consequences

Mammalian kidneys are specialized to maintain fluid and electrolyte homeostasis. The epithelial transport processes along the renal tubule that match output to input have long been the subject of experimental and theoretical study. However, emerging data have identified a new dimension of investigation: sex. Like most tissues, the structure and function of the kidney is regulated by sex hormones and chromosomes. Available data demonstrate sex differences in the abundance of kidney solute and electrolyte transporters, establishing that renal tubular organization and operation are distinctly different in females and males. Newer studies have provided insights into the physiological consequences of these sex differences. Computational simulations predict that sex differences in transporter abundance are likely driven to optimize reproduction, enabling adaptive responses to the nutritional requirements of serial pregnancies and lactation - normal life-cycle changes that challenge the ability of renal transporters to maintain fluid and electrolyte homeostasis. Later in life, females may also undergo menopause, which is associated with changes in disease risk. Although numerous knowledge gaps remain, ongoing studies will provide further insights into the sex-specific mechanisms of sodium, potassium, acid-base and volume physiology throughout the life cycle, which may lead to therapeutic opportunities. This Review summarizes our current understanding of sex differences in renal fluid and electrolyte transporters, based primarily on studies in rodents. The authors describe the physiological consequences of these differences, based on information from experimental studies and from model predictions, and discuss the differential impact of sex on transporter regulation by hormones, diet and acid-base status. Renal tubule organization differs in female compared with male rodents, notably in the abundance and expression of transporters in individual segments; generally, androgens regulate transporter abundance along the proximal tubule and oestrogens regulate transporter abundance along the distal tubule.Compared with males, female rats exhibit lower fractional reabsorption of sodium along the proximal nephron (associated with a lower activity of NHE3 and lower abundance of claudin2 and AQP1) and higher fractional reabsorption of sodium along distal segments (associated with a higher abundance of NKCC2, NCC, ENaC and phosphorylated AQP2).Female rats excrete a saline load more rapidly than males and achieve sodium homeostasis with a high salt diet more rapidly than males; moreover, female, but not male, diabetic mice maintain normotension when administered a high-salt diet.Angiotensin infusion provokes similar changes in blood pressure, ENaC activation and K+ loss in both sexes, along with a rise in the expression of distal renal tubule transporters and a lowering of proximal transporters in females.Male and female kidneys differ in the mechanisms used to maintain acid-base homeostasis; for example, they demonstrate differences in baseline ammoniagenesis and their acid-base transporters, and prioritize different adaptations to acid load; key differences are androgen receptor dependent.Computer simulations of pregnant rat kidney function indicate that known sex differences in renal transporters can serve to prepare females to meet the fluid and electrolyte demands of the offspring.