The human sodium-dependent ascorbic acid transporters SLC23A1 and SLC23A2 do not mediate ascorbic acid release in the proximal renal epithelial cell

Abstract

Sodium-dependent ascorbic acid membrane transporters SLC23A1 and SLC23A2 mediate ascorbic acid (vitamin C) transport into cells. However, it is unknown how ascorbic acid undergoes cellular release, or efflux. We hypothesized that SLC23A1 and SLC23A2 could serve a dual role, mediating ascorbic acid cellular efflux as well as uptake. Renal reabsorption is required for maintaining systemic vitamin C concentrations. Because efflux from nephron cells is necessary for reabsorption, we studied whether SLC23A1 and SLC23A2 mediate efflux of ascorbic acid in the human renal nephron. We found high gene expression of SLC23A1 but no expression of SLC23A2 in the proximal convoluted and straight tubules of humans. These data rule out SLC23A2 as the ascorbic acid release protein in the renal proximal tubular epithelia cell. We utilized a novel dual transporter-based Xenopus laevis oocyte system to investigate the function of the SLC23A1 protein, and found that no ascorbate release was mediated by SLC23A1. These findings were confirmed in mammalian cells overexpressing SLC23A1. Taken together, the data for SLC23A1 show that it too does not have a role in cellular release of ascorbic acid across the basolateral membrane of the proximal tubular epithelial cell, and that SLC23A1 alone is responsible for ascorbic acid uptake across the apical membrane. These findings reiterate the physiological importance of proper functioning of SLC23A1 in maintaining vitamin C levels for health and disease prevention. The ascorbate efflux mechanism in the proximal tubule of the kidney remains to be characterized.

The Association Between Ascorbate and the Hypoxia-Inducible Factors in Human Renal Cell Carcinoma Requires a Functional Von Hippel-Lindau Protein

“…The kidney has a unique distribution of sodium-dependent vitamin C transporters (SVCT1 and SVCT2). SVCT1 is situated in the brush-border membrane of proximal tubule cells where it is responsible for maintaining whole body ascorbate levels by mediating renal reabsorption, whereas SVCT2 is expressed basolaterally in all cells in the kidney except the proximal tubule ( 30 – 32 ). Both papillary and clear cell RCC are presumed to derive from the epithelium of the proximal tubule which only expresses SVCT1 ( 33 ).…”

Vitamin C: the known and the unknown and Goldilocks

“…Because vitamin C is an anion at physiologic pH, it cannot simply diffuse across the cell membrane to extracellular fluid. Efflux transporters for the vitamin have not been identified (Eck et al , ). For intestinal epithelium and proximal renal tubular cells, vitamin C is absorbed by luminal transporters such as SVCT1.…”

“…For rapid hormone‐dependent secretion of vitamin C to occur, a transport mechanism is likely to be responsible, but is as yet unidentified. Transport kinetics properties of SVCT1 and SVCT2 are ideal for transporting the vitamin into cells, but not for its secretion into plasma or extracellular fluids from cells (Eck et al , ).…”

Protective Role for Antioxidants in Acute Kidney Disease

“…Low plasma vitamin C is a risk factor for mortality and adverse cardiovascular events in hemodialysis patients [ 123 ], and AKI co-morbidities, such as diabetes, are associated with vitamin C deficiency [ 124 ]. The renal system is important in vitamin C re-absorption [ 125 ], and impairment may affect plasma ascorbate levels. Patients with renal dysfunction, such as septic, critically ill, and elderly, demonstrate low ascorbate levels [ 119 ], and bolstering vitamin C intake may prevent ROS-mediated renal damage in AKI.…”