Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice
Christopher P. Corpe, … , Michael Graham Espey, Mark Levine
Christopher P. Corpe, … , Michael Graham Espey, Mark Levine
Published March 1, 2010
Citation Information: J Clin Invest. 2010;120(4):1069-1083. https://doi.org/10.1172/JCI39191.
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Research Article Nephrology

Vitamin C transporter Slc23a1 links renal reabsorption, vitamin C tissue accumulation, and perinatal survival in mice

Abstract

Levels of the necessary nutrient vitamin C (ascorbate) are tightly regulated by intestinal absorption, tissue accumulation, and renal reabsorption and excretion. Ascorbate levels are controlled in part by regulation of transport through at least 2 sodium-dependent transporters: Slc23a1 and Slc23a2 (also known as Svct1 and Svct2, respectively). Previous work indicates that Slc23a2 is essential for viability in mice, but the roles of Slc23a1 for viability and in adult physiology have not been determined. To investigate the contributions of Slc23a1 to plasma and tissue ascorbate concentrations in vivo, we generated Slc23a1–/– mice. Compared with wild-type mice, Slc23a1–/– mice increased ascorbate fractional excretion up to 18-fold. Hepatic portal ascorbate accumulation was nearly abolished, whereas intestinal absorption was marginally affected. Both heterozygous and knockout pups born to Slc23a1–/– dams exhibited approximately 45% perinatal mortality, and this was associated with lower plasma ascorbate concentrations in dams and pups. Perinatal mortality of Slc23a1–/– pups born to Slc23a1–/– dams was prevented by ascorbate supplementation during pregnancy. Taken together, these data indicate that ascorbate provided by the dam influenced perinatal survival. Although Slc23a1–/– mice lost as much as 70% of their ascorbate body stores in urine daily, we observed an unanticipated compensatory increase in ascorbate synthesis. These findings indicate a key role for Slc23a1 in renal ascorbate absorption and perinatal survival and reveal regulation of vitamin C biosynthesis in mice.

Authors

Christopher P. Corpe, Hongbin Tu, Peter Eck, Jin Wang, Robert Faulhaber-Walter, Jurgen Schnermann, Sam Margolis, Sebastian Padayatty, He Sun, Yaohui Wang, Robert L. Nussbaum, Michael Graham Espey, Mark Levine

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Figure 1

Design, preparation, and confirmation of Slc23a1–/– mice.

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Design, preparation, and confirmation of Slc23a1–/– mice. (A) Northe...
(A) Northern blot analysis of mouse Slc23a1 gene expression. Multitissue mouse Northern blot panel probed with [α32P]-d-CTP–labeled mouse Slc23a1 cDNA (top), normalized to β-actin gene expression (bottom). (B) Genomic DNA PCR analyses. DNA obtained from Slc23a1+/+, Slc23a1+/–, and Slc23a1–/– littermates was analyzed by PCR. The wild-type allele was predicted to be a 3-kb fragment; the deletion allele was predicted to be a 10-kb fragment. M, DNA marker standards. (C) RT-PCR analysis of Slc23a1 gene expression in progeny from heterozygous crosses. Gene expression was assessed in liver, kidney, and small intestine from Slc23a1+/+, Slc23a1+/–, and Slc23a1–/– mice. A 366-bp fragment was amplified by RT-PCR in Slc23a1+/+ and Slc23a1+/– RNA, but not in RNA isolated from Slc23a1–/– mice. As an internal control, gene expression of Gapdh was assessed by amplifying a 900-bp GAPDH PCR product in all tissues analyzed. bl, blank control; st, DNA standards. (D) Body weight as a function of time in Slc23a1+/+, Slc23a1+/–, and Slc23a1–/– mice. Female (n = 3–19) and male (n = 4–29) littermates were weighed at weaning (3 weeks) and weekly thereafter. P = NS.