McDonough Alicia A, Foley Trinity S, Ralph Donna L, Schwindt Seth, Soong Joanne, Carrisoza-Gaytan Rolando, Lasaad Samia, Nelson Jonathan W, Edwards Aurelie, Kleyman Thomas R, Satlin Lisa M
Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, California, United States.
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, United States.
Am J Physiol Renal Physiol. 2025 May 1;328(5):F638-F646. doi: 10.1152/ajprenal.00017.2025. Epub 2025 Mar 10.
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 (mNKAα1), medullary beta1 subunit of sodium-potassium ATPase (mNKAβ1), sodium-chloride cotransporter, and epithelial sodium channel (ENaC) β and -γ 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. We used the four core genotypes (FCG) mouse model to compare abundance of more than 50 renal transporters and regulators in: FXX gonadal females, FXY gonadal females, MXX Sry males, and MXY XY Sry males using semiquantitative immunoblots. In addition to establishing the significant influence of gonadal hormones, we show, for the first time, that sex chromosome complement (SCC) contributes to sexual dimorphisms in abundance of many renal transporters.
肾小管盐和水转运蛋白、通道、紧密连接蛋白及调节因子的性别差异在整个肾单位中都很明显。通过去除、抑制或恢复性激素及其受体的研究，已证实性激素对生理形态差异的影响。性染色体组成（SCC，XY与XX）对肾转运蛋白丰度和活性的影响仍是一个未解决的问题。我们使用四核心基因型（FCG）小鼠模型（其中决定睾丸的SRY基因从Y染色体上删除并插入到常染色体上），通过半定量免疫印迹法比较了以下小鼠中50多种肾转运蛋白和调节因子的丰度：FXX性腺雌性小鼠、FXY性腺雌性小鼠、MXX Sry雄性小鼠和MXY XYSry雄性小鼠。除了证实性腺激素的显著影响外，我们首次表明，性染色体组成（SCC）导致了许多肾转运蛋白丰度的性别差异，这些转运蛋白包括：钠/氢交换体3型（NHE3）、钠葡萄糖共转运蛋白1（SGLT1）、钠葡萄糖共转运蛋白2（SGLT2）、水通道蛋白1（AQP1）、钠钾ATP酶髓质α1亚基（mNKAα1）、钠钾ATP酶髓质β1亚基（mNKAβ1）、氯化钠共转运蛋白以及上皮钠通道（ENaC）β和γ亚基。该FCG模型分析的结果为未来研究性激素与染色体在生理参数（包括滤过和血流）、转运蛋白共价修饰以及健康和疾病状态下的转运方面的作用奠定了基础。我们使用四核心基因型（FCG）小鼠模型，通过半定量免疫印迹法比较了FXX性腺雌性小鼠、FXY性腺雌性小鼠、MXX Sry雄性小鼠和MXY XY Sry雄性小鼠中50多种肾转运蛋白和调节因子的丰度。除了证实性腺激素的显著影响外，我们首次表明，性染色体组成（SCC）导致了许多肾转运蛋白丰度的性别差异。
