Functional implications of sexual dimorphism of transporter patterns along the rat proximal tubule: modeling and...

The goal of this study is to investigate the functional implications of the sexual dimorphism in transporter patterns along the proximal tubule. To do so, we have developed sex-specific computational models of solute and water transport in the proximal convoluted tubule of the rat kidney. The models account for the sex differences in expression levels of the apical and basolateral transporters, in single-nephron glomerular filtration rate, and in tubular dimensions. Model simulations predict that 70.6 and 38.7% of the filtered volume is reabsorbed by the proximal tubule of the male and female rat kidneys, respectively. The lower fractional volume reabsorption in females can be attributed to their smaller transport area and lower aquaporin-1 expression level. The latter also results in a larger contribution of the paracellular pathway to water transport. Correspondingly similar fractions (70.9 and 39.2%) of the filtered Na⁺ are reabsorbed by the male and female proximal tubule models, respectively. The lower fractional Na⁺ reabsorption in females is due primarily to their smaller transport area and lower Na⁺/H⁺ exchanger isoform 3 and claudin-2 expression levels. Notably, unlike most Na⁺ transporters, whose expression levels are lower in females, Na⁺-glucose cotransporter 2 (SGLT2) expression levels are 2.5-fold higher in females. Model simulations suggest that the higher SGLT2 expression in females may compensate for their lower tubular transport area to achieve a hyperglycemic tolerance similar to that of males.