Functional implications of the sex differences in transporter abundance along the rat nephron: modeling and analysis

The goal of the present study was to investigate the functional implications of sexual dimorphism in the pattern of transporters along the rodent nephron as reported by Veiras et al. (J Am Soc Nephrol 28: 3504-3517, 2017). To do so, we developed sex-specific computational models of water and solute transport along the superficial nephrons from male and female rat kidneys. The models account for the sex differences in the abundance of apical and basolateral transporters, single nephron glomerular filtration rate, and tubular dimensions. Model simulations predict that ~70% and 60% of filtered Na⁺ is reabsorbed by the proximal tubule of male and female rat kidneys, respectively. The lower fractional Na⁺ reabsorption in female kidneys is due primarily to their smaller transport area, lower Na⁺/H⁺ exchanger activity, and lower claudin-2 abundance, culminating in significantly larger fractional delivery of water and Na⁺ to the downstream nephron segments in female kidneys. Conversely, the female distal nephron exhibits a higher abundance of key Na⁺ transporters, including Na⁺-K⁺-Cl^- cotransporters, Na⁺-Cl^- cotransporters, and epithelial Na⁺ channels. The higher abundance of transporters accounts for the enhanced water and Na⁺ transport along the female, relative to male, distal nephron, resulting in similar urine excretion between the sexes. Consequently, in response to a saline load, the Na⁺ load delivered distally is greater in female rats than male rats, overwhelming transport capacity and resulting in higher natriuresis in female rats.