Sex Differences in Acidosis‐Stimulated Renal Ammonia Metabolism

Abstract

Renal ammonia excretion is a critical component in maintaining acid‐base homoeostasis and changes in ammonia excretion are the predominant component of increased net acid excretion in response to metabolic acidosis. We reported recently substantial sex‐dependent differences in basal ammonia metabolism that correlate with sex‐dependent structural differences and differences in the expression of key proteins involved in ammonia metabolism. This study's objective was to determine the effect of sex on the renal ammonia response to an exogenous acid load. We compared 4‐month old C57BL/6 male (M) and female (F) mice. Mice were acid‐loaded by adding HCl to powdered chow for 7 days, and control mice had equal amounts of deionized water added. Basal ammonia excretion, factored for body weight, was ~2‐fold greater in female than male mice, but the response to acid‐loading did not differ significantly. There was no significant sex difference in serum Na+, K+, and HCO3− after an acid load. The basal fundamental structural differences between the female and male kidney were maintained after an acid load. After acid‐loading, in the female kidney, proximal tubules account for a lower percentage of the cortical parenchyma than in the male kidney (F, 43±2; M, 61±3%; P < 0.001), whereas the collecting ducts account for a greater percentage of the renal parenchyma (F, 16±1; M, 11±1%; P < 0.01) which are similar to basal conditions. Cortical PCT and PST cell height increased in response to acid‐loading, and the increase was greater in M than F kidney. In the outer medulla (OM), PST cell height was similar in M and F, and sex did not alter the increase with acid‐loading. Similarly, intercalated cell (IC) size in the collecting duct in the OM was greater in F than in M kidney, and increased with acid‐loading in both sexes; sex did not alter the acid‐loading increase. Cortical expression of phosphoenol pyruvate, a major proximal tubule (PT) ammonia generating protein, was greater under control conditions in F, but the relative increase with acid‐loading was greater in M. Expression of glutamine synthetase, which recycles ammonia, significantly decreased in response to an acid load, with no significant sex difference. Expression of total cortical NBCe1, but not NBCe1‐A, increased in response to acid‐loading. Expression of NHE3, believed to be the major mechanism of PT ammonia secretion, increased in response to an acid load in M, but not in F. Cortical NKCC2, which mediates thick ascending limb ammonia reabsorption, was significantly greater in F than M after an acid load. The collecting duct secretes the majority of urinary ammonia and the Rhesus glycoproteins, Rhbg and Rhcg, are the primary collecting duct ammonia transporting proteins. Acid‐loading increased cortical Rhbg expression in M, but not in F in the cortex, whereas in the OM, Rhbg expression increased similarly in both M and F. Rhcg expression in intercalated cells in the inner stripe of the outer medulla was significantly greater in F than in M mice after an acid load. We conclude that there are substantial sex‐dependent differences in the mechanism of renal ammonia response to acid‐loading that enable a similar maximum ammonia excretion response.Support or Funding InformationNIH R01DK045788, R01DK107798 and 5T32DK104721This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.