KCC3a regulation in the distal nephron displays sexual dimorphism

Sex differences in renal physiology are well established, particularly in distal nephron sodium and potassium handling. Females exhibit greater Na⁺-Cl⁻ cotransporter (NCC) activity in the distal convoluted tubule compared with males. Metabolic alkalosis, common during diuretic therapy, chloride-depleting states, and mineralocorticoid excess, further challenges distal nephron electrolyte regulation. We previously identified the apical K⁺-Cl⁻ cotransporter isoform a (KCC3a) in bicarbonate-secreting intercalated cells as a bicarbonate-responsive pathway linked to distal transport coupling during alkalemia. Here, we tested whether KCC3a regulation during alkalemia is sex dependent. Male and female C57BL/6J mice were treated with NaHCO₃ or NaCl for 10 days. Bicarbonate loading increased renal KCC3a protein abundance in males but not females, despite similar baseline expression and unchanged mRNA levels. Ovariectomy did not alter the female response, whereas orchiectomy abolished KCC3a upregulation in males, consistent with gonadal hormone effects supported by the four core genotypes model. Reintroduction of 5α-dihydrotestosterone only partially rescued KCC3a upregulation during bicarbonate challenge in orchiectomized mice. These findings identify KCC3a as a male hormone-permissive component of renal adaptation to alkalemia and reveal sex-specific regulation of bicarbonate-responsive transport pathways.