Testosterone Modulates Renal Ammonia Metabolism.

There are substantial sex differences in renal structure and ammonia metabolism that correlate with differences in expression of proteins involved in ammonia generation and transport. This study determined the role of testis-derived testosterone in these differences. We studied 4 month-old C57BL/6 male mice 4 and 8 weeks after either bilateral orchiectomy (ORCH) or sham-operated control (SOC) surgery, and we determined the effect of testosterone replacement to reverse the effects of ORCH (ORCH+T). Finally, we determined the cellular expression of androgen receptor (AR), testosterone's canonical target receptor. ORCH decreased kidney and proximal tubule size, and testosterone-replacement reversed this effect. ORCH increased ammonia excretion in a testosterone-dependent fashion; this occurred despite similar food intake, which is the primary component of endogenous acid production. ORCH increased expression of both phosphoenolpyruvate (PEPCK), a major ammonia generating protein, and NKCC2, which mediates thick ascending limb (TAL) ammonia reabsorption; these changes were reversed with testosterone replacement. Orchiectomy also decreased expression of NHE-3, which mediates proximal tubule ammonia secretion, in a testosterone-dependent pattern. Finally, AR is expressed throughout the proximal tubule in both the male and female kidney. Testosterone, possibly acting through AR, has dramatic effects on kidney and proximal tubule size, and decreases ammonia excretion through its effects on several key proteins involved in ammonia metabolism.