Effect of sex chromosome complement versus gonadal hormones on abundance of renal transporters

Sex differences in renal tubular salt and water transporters, channels, claudins, and regulatory factors are evident all along the nephron. The influence of sex hormones on physiologic dimorphisms has been established in studies removing, inhibiting, or restoring sex hormones and their receptors. The influence of the sex chromosome complement (SCC, XY vs. XX) on renal transporter abundance and activity is an open question. We used the four core genotypes (FCG) mouse model (in which the testis determining SRY gene is deleted from the Y chromosome and inserted onto an autosomal chromosome) to compare abundance of more than 50 renal transporters and regulators in: FXX gonadal females, FXY gonadal females, MXX Sry males, and MXY XYSry males using semiquantitative immunoblots. In addition to establishing the significant influence of gonadal hormones, we show, for the first time, that SCC contributes to sexual dimorphisms in abundance of renal transporters including: sodium/hydrogen exchanger isoform 3 (NHE3), sodium glucose cotransporter 1 (SGLT1), sodium glucose cotransporter 2 (SGLT2), aquaporin 1 (AQP1), medullary alpha1 subunit of sodium-potassium ATPase (mNKAa1), medullary beta1 subunit of sodium-potassium ATPase (mNKAb1), sodium-chloride cotransporter, and epithelial sodium channel (ENaC) b and -c subunits. The findings in this FCG model analysis provide the foundation for future studies of the role of sex hormones versus chromosomes on physiologic parameters, including filtration and flow, on transporter covalent modifications, and trafficking in both health and disease.