Effect of NBCe1 deletion on renal citrate and 2-oxoglutarate handling.

Gunars Osis,Weitao Huang,Kathleen S Hering-Smith,I David Weiner,Michael F Romero,Jill W Verlander,Hyun-Wook Lee,Mary E Handlogten

doi:10.14814/phy2.12778

Abstract

The bicarbonate transporter, NBCe1 (SLC4A4), is necessary for at least two components of the proximal tubule contribution to acid‐base homeostasis, filtered bicarbonate reabsorption, and ammonia metabolism. This study's purpose was to determine NBCe1's role in a third component of acid‐base homeostasis, organic anion metabolism, by studying mice with NBCe1 deletion. Because NBCe1 deletion causes metabolic acidosis, we also examined acid‐loaded wild‐type adult mice to determine if the effects of NBCe1 deletion were specific to NBCe1 deletion or were a non‐specific effect of the associated metabolic acidosis. Both NBCe1 KO and acid‐loading decreased citrate excretion, but in contrast to metabolic acidosis alone, NBCe1 KO decreased expression of the apical citrate transporter, NaDC‐1. Thus, NBCe1 expression is necessary for normal NaDC‐1 expression, and NBCe1 deletion induces a novel citrate reabsorptive pathway. Second, NBCe1 KO increased 2‐oxoglutarate excretion. This could not be attributed to the metabolic acidosis as experimental acidosis decreased excretion. Increased 2‐oxoglutarate excretion could not be explained by changes in plasma 2‐oxoglutarate levels, the glutaminase I or the glutaminase II generation pathways, 2‐oxoglutarate metabolism, its putative apical 2‐oxoglutarate transporter, OAT10, or its basolateral transporter, NaDC‐3. In summary: (1) NBCe1 is necessary for normal proximal tubule NaDC‐1 expression; (2) NBCe1 deletion results in stimulation of a novel citrate reabsorptive pathway; and (3) NBCe1 is necessary for normal 2‐oxoglutarate metabolism through mechanisms independent of expression of known transport and metabolic pathways.

Highlights

Renal acid-base homeostasis involves multiple interdependent mechanisms
NBCe1 deletion was associated with a significant decrease in citrate excretion (WT, 305 Æ 97 lg/mg creatinine; vs KO, 0.0 Æ 0.0 lg/mg creatinine; n = 5 in each group; P < 0.02). 2-oxoglutarate excretion, in contrast, was significantly increased in mice with NBCe1 deletion as compared to wild-type mice (WT, 36.5 Æ 18.5 lg/mg creatinine; vs. KO, 557.7 Æ 51.2 lg/ mg creatinine; n = 5 in each group; P < 0.001)
In wild-type mice, metabolic acidosis decreased both citrate and 2-oxoglutarate excretion (WT, 5.15 Æ 1.90 lg per 24 h; vs. acidosis, 0.83 Æ 0.17 lg per 24 h; n = 5 in each group; P < 0.05) significantly. These findings indicate that the effects of NBCe1 deletion on citrate excretion are similar to those observed with metabolic acidosis, but that the effects on 2oxoglutarate excretion are diametrically different

Summary

Introduction

Renal acid-base homeostasis involves multiple interdependent mechanisms. These include filtered bicarbonate reabsorption, intrarenal ammonia metabolism and transport, and excretion of organic anions, such as citrate and 2-oxoglutarate (Palmer and Alpern 2010; Weiner and Verlander 2012; Hamm et al 2013; Weiner et al 2013).Each has a critical role in multiple components of renal physiology. Renal acid-base homeostasis involves multiple interdependent mechanisms. These include filtered bicarbonate reabsorption, intrarenal ammonia metabolism and transport, and excretion of organic anions, such as citrate and 2-oxoglutarate (Palmer and Alpern 2010; Weiner and Verlander 2012; Hamm et al 2013; Weiner et al 2013). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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Conclusion