Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney

Fang, Liangjuan; Lee, Hyun‐Wook; Chen, Chao; Harris, Autumn N.; Romero, Michael F.; Verlander, Jill W.; Weiner, I. David

doi:10.1152/ajprenal.00515.2017

Cited by 19 publications

(30 citation statements)

References 62 publications

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“…We have recently identified that NBCe1, a basolateral proximal tubule Na ϩbicarbonate cotransporter, regulates proximal tubule ammonia metabolism (18,31). Two splice variants of NBCe1, NBCe1-A and NBCe1 variant B (NBCe1-B), are present in the kidney (9,31). We have previously shown that there are no significant sex differences in NBCe1 expression under basal conditions (20).…”

Section: F893mentioning

confidence: 99%

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Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney

Harris

Lee

Fang

et al. 2019

American Journal of Physiology-Renal Physiology

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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 c...

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Section: F893mentioning

confidence: 99%

“…Two of these variants are expressed in the kidney. The A variant is expressed at high levels in the renal proximal tubule basolateral plasma membrane, whereas the B variant is expressed in the mouse renal proximal tubule at apparently much lower levels (9). Thus, we next evaluated the NBCe1-A response to acid loading.…”

Section: F893mentioning

confidence: 99%

Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney

Harris

Lee

Fang

et al. 2019

American Journal of Physiology-Renal Physiology

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“…Finally, in reference to a recent report of Nbce1b expression in the renal medulla, 9 the ability of the kidneys to maintain an apparently appropriately elevated plasma [HCO 3 2 ] does…”

Section: The Role Of Renal Nbce1bmentioning

confidence: 99%

“…, either to maintain intracellular pH (e.g., in neurons) or to support transepithelial anion/fluid secretion (e.g., in gastrointestinal epithelia). [7][8][9] NBCe1-A and NBCe1-B/C differ not only in their distribution but also in their Nt and Ct sequences; NBCe1-A includes a unique 41 amino-acid autostimulatory domain (encoded by the orange section of exon 4 in Figure 1A), whereas NBCe1-B/C include in its place an 85 amino-acid autoinhibitory domain (encoded by exons 2 and 3; blue in in Figure 1A). 10 The consequence of these alternative Nt sequences is that NBCe1-A exhibits a greater conductance than NBCe1-B/C.…”

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confidence: 99%

Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice

Salerno

Patel

Marshall

et al. 2019

JASN

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BackgroundThe SLC4A4 gene encodes electrogenic sodium bicarbonate cotransporter 1 (NBCe1). Inheritance of recessive mutations in SLC4A4 causes proximal renal tubular acidosis (pRTA), a disease characterized by metabolic acidosis, growth retardation, ocular abnormalities, and often dental abnormalities. Mouse models of pRTA exhibit acidemia, corneal edema, weak dental enamel, impacted colons, nutritional defects, and a general failure to thrive, rarely surviving beyond weaning. Alkali therapy remains the preferred treatment for pRTA, but it is unclear which nonrenal signs are secondary to acidemia and which are a direct consequence of NBCe1 loss from nonrenal sites (such as the eye and enamel organ) and therefore require separate therapy. SLC4A4 encodes three major NBCe1 variants: NBCe1-A, NBCe1-B, and NBCe1-C. NBCe1-A is expressed in proximal tubule epithelia; its dysfunction causes the plasma bicarbonate insufficiency that underlies acidemia. NBCe1-B and NBCe1-C exhibit a broad extra-proximal-tubular distribution.MethodsTo explore the consequences of Nbce1b/c loss in the absence of acidemia, we engineered a novel strain of Nbce1b/c-null mice and assessed them for signs of pRTA.ResultsNbce1b/c-null mice have normal blood pH, but exhibit increased mortality, growth retardation, corneal edema, and tooth enamel defects.ConclusionsThe correction of pRTA-related acidemia should not be considered a panacea for all signs of pRTA. The phenotype of Nbce1b/c-null mice highlights the physiologic importance of NBCe1 variants expressed beyond the proximal tubular epithelia and potential limitations of pH correction by alkali therapy in pRTA. It also suggests a novel genetic locus for corneal dystrophy and enamel hypomineralization without acidemia.

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“…Three variants, NBCe1-A, NBCe1-B and NBCe1-C, are present in both humans and in rodents, and two, NBCe1-D and NBCe1-E, have to date been identified only in rodents. Only two of these variants, NBCe1-A and NBCe1-B appear to be expressed in the kidney (74,75) . NBCe1-A is the more highly expressed of the two, and is found exclusively in cortical proximal tubule segments, whereas…”

Section: Regulation By Nbce1mentioning

confidence: 99%

Emerging Features of Ammonia Metabolism and Transport in Acid-Base Balance

Weiner

Verlander

2019

Seminars in Nephrology

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Ammonia metabolism has a critical role both in acid-base homeostasis and in other cellular functions. Kidneys have a central role in bicarbonate generation, which occurs through the process of net acid excretion; ammonia metabolism is the quantitatively greatest component of net acid excretion, both under basal conditions and in response to acid-base disturbances. Several recent studies have substantially advanced our understanding of the molecular mechanisms and regulation of ammonia metabolism. First, the previous paradigm that ammonia transport could be explained by passive NH 3 diffusion and NH 4 + trapping has been advanced by the recognition that specific transport of NH 3 and of NH 4 + by specific membrane proteins is critical to ammonia transport. Second, significant advances have been made in the understanding of the regulation of ammonia metabolism. Novel studies show that hyperkalemia directly inhibits ammonia metabolism, thereby leading to the metabolic acidosis present in Type IV RTA. Other studies show that the proximal tubule protein, NBCe1, and specifically the A variant, NBCe1-A, have a major role regulating renal ammonia metabolism. Thirdly, there are important sex differences in ammonia metabolism that involve structural and functional differences in the kidney. In this review we discuss these important aspects of the emerging features of ammonia metabolism and transport.

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Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney

Cited by 19 publications

References 62 publications

Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney

Differences in acidosis-stimulated renal ammonia metabolism in the male and female kidney

Extrarenal Signs of Proximal Renal Tubular Acidosis Persist in Nonacidemic Nbce1b/c-Null Mice

Emerging Features of Ammonia Metabolism and Transport in Acid-Base Balance

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