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

Abstract

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.

Keywords: NHE3; SGLT2; epithelial transport; sex difference; sodium transport.

Fig. 1.

Schematic diagram of the proximal convoluted cell model, showing major Na⁺, K⁺, and Cl⁻ transport pathways. Flux values computed at the midpoint of the proximal convoluted tubule are shown in blue and red for male and female rats, respectively.

Fig. 2.

A–G: solute flow profiles along the proximal tubule of the male (solid lines) and female (dashed lines) rat kidney. H: tubular fluid pH. I: water flow profile. Substantially less Na⁺, K⁺, Cl⁻, and water is reabsorbed along the female rat proximal tubule compared with the male. TA, titratable acid.

Fig. 3.

Changes in fractional Na⁺ reabsorption (ΔF_Na) along the proximal tubule of the male rat, when individual parameters are set to female rat values. The lower single-nephron glomerular filtration rate (SNGFR) in the female increases ΔF_Na because of the lower filtered load, even though absolute Na⁺ reabsorption decreases. AQP1, aquaporin-1; Cldn2, claudin-2; NaPi2, Na⁺-phosphate cotransporter 2; NHE3, Na⁺/H⁺ exchanger isoform 3; SGLT2, Na⁺-glucose cotransporter 2.

Fig. 4.

Glucose transport along the proximal tubule of the male (blue) and female (red) rat kidney at differing hyperglycemic levels ([G]). A: tubular glucose flow at selected [G]. B: fractional glucose reabsorption as a function of [G]. Glucosuria occurs at similar hyperglycemic level for male and female rats. C: proximal tubular Na⁺ outflow as a function of [G]. D: proximal tubular water outflow as a function of [G]. As [G] increases, fractional reabsorption of both Na⁺ and water decreases. PCT, proximal convoluted tubule.

Fig. 5.

Effects of variations in single-nephron glomerular filtration rate (SNGFR) on proximal tubular transport. As SNGFR is varied from 30% below baseline to 30% above, fluid flow (A), Na⁺ flow (B), and glucose flow (C) at the proximal tubule outlet increase. Male and female rat proximal tubule models exhibit similar tolerance to elevated glucose load due to hyperfiltration.