Deletion of the Proximal Tubule Basolateral Bicarbonate Transporter, NBCe1, Impairs Ammonia Metabolism

Abstract

Metabolic acidosis typically increases ammonia excretion, but people with proximal renal tubular acidosis (pRTA), despite acidosis, do not have increased ammonia excretion. Genetic forms of human pRTA typically involve the proximal tubule bicarbonate transporter, NBCe1. This study's purpose was to determine NBCe1's role in renal ammonia metabolism. We used previously reported mice with NBCe1 deletion. Because -/- mice have 100% mortality between d10-21, we studied mice at d8±1. Serum HCO3 was 26.4±1.0 in wild type (WT), 19.8±1.9 in heterozygous (het), and 10.3±0.6 mM in homozygous knockout (KO) mice (P<0.05). Thus, NBCe1 deletion causes metabolic acidosis by d8. Urine pH was 5.3±0.2, 4.8±0.1 and 4.2±0.1 in WT, het and KO mice, respectively (P<0.01), indicating intact urine acidification and no ongoing HCO3 loss. Although acidosis normally increases ammonia excretion, NBCe1 deletion decreased ammonia excretion: 275±44, 212±11 and 94±69 mmol/g creatinine in WT, het and KO mice, respectively (P<0.01). Also, regulation of key proteins in ammonia metabolism was not typical of acidosis. NBCe1 deletion altered expression of multiple proximal tubule proteins (decreased PDG, PEPCK and NHE3 and increased glutamine synthetase expression). This pattern is the exact opposite of that expected with acidosis. Expression of the TAL ammonia transporter, NKCC2, and the collecting duct transporters, Rhbg and Rhcg, was unchanged. We conclude: 1) NBCe1 deletion inhibits proximal tubule ammonia metabolism, leading to decreased urinary ammonia excretion; and, 2) NBCe1, in addition to its role in HCO3 transport, may have an important role in ammonia metabolism.