Role of Proximal Tubule NHE3 in Ammonium and Krebs Cycle Metabolite Excretion

Abstract

The apical renal sodium hydrogen ion exchanger NHE3 plays an important role in several physiologic processes: bicarbonate (HCO3) reabsorption, Na reabsorption, BP regulation, and ammonium (Amm) excretion (via Na/NH4+ exchange). NHE3 knockout has also been proposed to alter renal metabolism. However, several aspects are unknown, particularly in providing a link between metabolism and transport. The present study addresses the role of the apical proximal tubule NHE3 in both overall Amm and Krebs cycle metabolite excretion. We hypothesized that Proximal Tubule specific NHE3 KO (PT-KO) could alter excretion of Krebs cycle metabolites since these are reabsorbed exclusively in the proximal tubule and their excretion is usually very sensitive to acid-base status & metabolism. Wild type (WT) & PT-KO mice were used and fed Normal diet or diet with 0.4 M HCl acid added for 72 hrs. As per previous reports, PT-KO in mice on a Normal diet did not lower blood pH or alter urinary Krebs cycle metabolites (citrate, succinate, & αKG); but urinary Amm significantly decreased in both males & females PT-KO, p < 0.02. Acid loading reduced plasma HCO3 but increased urinary Amm (p < 0.01) comparably in both WT & PT-KO. In contrast to some reports, acid loading significantly reduced urinary citrate, succinate, & αKG in both WT and PT-KO mice, shown in Figure 1. Thus, on Normal diet PT-KO (both males & females) resulted in lower urinary Amm but on Acid diet had appropriately higher urinary Amm excretion. Despite PT-KO, acid loads still reduced the excretion of all 3 of the Krebs cycle metabolites tested. These results indicate compensation of both metabolism and transporters sensitive to acid-base status.