Sex and species differences in epithelial transport in rat and mouse kidneys: Modeling and analysis

The goal of this study was to investigate the functional implications of sex and species differences in the pattern of transporters along nephrons in the rat and mouse kidney, as reported by Veiras et al. (J Am Soc Nephrol 28: 3504-3517, 2017). To do so, we developed the first sex-specific computational models of epithelial water and solute transport along the nephrons from male and female mouse kidneys, and conducted simulations along with our published rat models. These models account for the sex differences in the abundance of apical and basolateral transporters, glomerular filtration rate, and tubular dimensions. Model simulations predict that 73% and 57% of filtered Na⁺ is reabsorbed by the proximal tubules of male and female rat kidneys, respectively. Due to their smaller transport area and lower NHE3 activity, the proximal tubules in the mouse kidney reabsorb a significantly smaller fraction of the filtered Na⁺, at 53% in male and only 34% in female. The lower proximal fractional Na⁺ reabsorption in female kidneys of both rat and mouse 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⁺-Cl^- cotransporters in both species, epithelial Na⁺ channels for the female rat, and Na⁺-K⁺-Cl^-cotransporters for the female mouse. The higher abundance of transporters accounts for the enhanced water and Na⁺ transport along the female rat and mouse distal nephrons, relative to the respective male, resulting in similar urine excretion between the sexes. Model simulations indicate that the sex and species differences in renal transporter patterns may partially explain the experimental observation that, in response to a saline load, the diuretic and natriuretic responses were more rapid in female rats than males, but no significant sex difference was found in mice. These computational models can serve as a valuable tool for analyzing findings from experimental studies conducted in rats and mice, especially those involving genetic modifications.