Differential Effects of Sry and Y Chromosomes on Sexual Dimorphisms in Renal Ammonia Metabolism

Renal ammonia metabolism plays a critical role in maintaining acid-base balance through net acid excretion, particularly in patients with kidney disease. There are sexual dimorphisms in renal ammonia metabolism and structure, some, but not all, of which are mediated through androgen receptor-dependent signaling pathways. This study’s objective was to determine the role of sex chromosomes as opposed to sex hormones in these sexual dimorphisms. We used four-core genotype mice, which have the sex-hormone determining Sry gene deleted from the Y chromosome and re-expressed on chromosome 3. As a result, the role of the Sry gene can be determined separately from other sex genes on the Y chromosome. We used 2-way ANOVA to separately determine the role of the Sry-gene and the Y-chromosome on renal ammonia metabolism and structure. Mice with absence of the Sry gene (Sry-neg) had increased ammonia excretion compared to mice with the Sry gene independent of the presence or absence of the Y chromosome (Sry-neg XX, 73±7 µmol/day; Sry-neg XY, 85±38; Sry-pos XX, 21±4; Sry-pos XY, 31±8; p<0.01 for Sry, N=6 in each group). The presence or absence of the Y chromosome did not independently alter ammonia excretion (P=NS). Although renal structural size typically parallels ammonia excretion, Sry-neg mice had decreased left kidney renal size, and XX vs XY did not significantly alter renal size (Sry-neg XX, 156±11 mg, Sry-neg XY, 142±14, Sry-pos XX, 195±14, Sry-pos XY, 196±8; p<0.01; N=6 in each group). Similarly, cortical proximal tubule volume density (PT-VD) was Sry-dependent and Y chromosome-independent (Sry-neg XX, 43%±1%, Sry-neg XY, 41%±2%; Sry-pos XX, 63%±1%; Sry-pos XY, 63%±1%; p<0.01 for Sry; P=NS for XX v XY; N=6 in each group). Expression of phosphoenolpyruvate carboxykinase (PEPCK), a major proximal tubule (PT) ammonia-generating protein, was increased significantly by the absence of Sry in both XX and XY mice and was unaffected by XY. There were no significant alterations in NHE3, a major mechanism of PT ammonia secretion, NBCe1-A, a basolateral PT transporter that regulates PT ammonia metabolism, or collecting duct Rhbg expression. These effects occurred even though there were no alterations in food intake, urine pH, or serum Na+ or K + concentrations. We conclude the four-core genotype model enables separate assessment of sex steroid hormones and the Y-chromsome on renal structure and function. Sex steroid hormones, but not the Y-chromosome, mediate a major role in sexual dimorphisms in renal ammonia excretion, renal structure, and some, but not all, proteins involved in ammonia generation. NIH- NIDDK - K08-DK12087 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.