Renal Tubular Reabsorption of Folate Mediated by Folate Binding Protein 1

Abstract

Renal tubular reabsorption of filtered folate is essential for the conservation and normal homeostasis of this important vitamin. Different molecular mechanisms have been implicated in epithelial folate transport, including folate receptors. Defective expression or antibody inactivation of these is associated with embryonic defects also correlated with low folate intake; however, their contribution to renal tubular folate reabsorption has not been established. With the use of targeted inactivation of the folate binding protein 1 (folbp1) and folate binding protein 2 (folbp2) genes in mice, the role of folate receptors in renal epithelial folate reabsorption was evaluated during low and normal folate intake. Inactivation of folbp1 was associated with (1) loss of 3 H-folic acid binding to crude kidney membranes, (2) increase in renal folate clearance, and (3) increase in urinary excretion and decrease in renal uptake of injected 3 H-methyltetrahydrofolate. No changes in renal folate handling were observed as a result of folbp2 inactivation. Thus, folbp1 is essential for normal renal tubular folate reabsorption, preventing excessive urinary folate loss. Folbp1 is heavily expressed in choroid plexus, yolk sac, and placenta, supporting a role of folbp1 in folate transport in other tissues. The greatest significance of folbp1 for renal folate uptake was observed at conditions of low folate intake, providing a possible explanation for the ability of folate supplementation to prevent developmental defects associated with folbp1 inactivation.

Folate Receptor–Targeted Antioxidant Therapy Ameliorates Renal Ischemia–Reperfusion Injury

“…The presence of folate receptor-a expression in the proximal tubule was demonstrated previously by Birn et al 25 Tempolfolate is designed to be membrane impermeable and therefore have low accumulation in nontarget organs. However, we hypothesized that it would accumulate in the kidney due to the high expression of the folate receptor and would subsequently be transported across the basolateral membrane into the kidney.…”

“…Folic acid is an essential vitamin with a high affinity for the folate receptor, which maintains folate homeostasis. 25,26 The selectively expressed folate receptor allows for passage of folate into the cell by encapsulation into clathrin-coated pits. 27 Folate is absorbed by the kidney, predominantly in the proximal tubule, which fortuitously is a site particularly at risk during ischemia.…”

“…28 The binding of folate to the folate receptor occurs at a relatively high affinity with half maximal binding as high as 12 nM in human proximal tubule cells, making it ideal for pharmacological targeting. 25,26,29 In this study, we synthesized a novel folate-antioxidant conjugate to selectively target the kidney, to enhance localized superoxide scavenging, and to prevent the development of ARF while avoiding the associated side effects of systemic antioxidant therapy. [16][17][18]30,31 We hypothesize that the tempol-folate conjugate selectively targets the renal proximal tubule and protects from ischemic injury by way of scavenging reactive oxygen species, therefore preventing the cascade of events resulting in tubular dysfunction and ARF ( Figure 1A).…”

A mouse model of hereditary folate malabsorption: deletion of the PCFT gene leads to systemic folate deficiency

“…7 The role of FOLR1 in folate absorption and transport has also been demonstrated, where a 60% to 70% reduction was observed in plasma folate of FOLR1 Ϫ/Ϫ mice fed low folate and normal chow. 12 FOLR1 also regulates folate homeostasis via endocytotic mechanisms during embryonic development, and mice rendered null for this receptor display severe morphogenetic abnormalities and die in utero unless provided supraphysiologic concentrations of either folinic acid or 5-methyltetrahydrofolate. 5,13 The PCFT transporter is highly expressed in tissues involved in folate and heme transport, including the duodenum and liver.…”

Folic acid transport via high affinity carrier-mediated system in human retinoblastoma cells

“…However, uptake mechanism and translocation of folic acid into the neural retina are not well understood despite its critical role in the growth and development of retina. Although many studies have focused on the mechanism of folic acid uptake in various tissues such as intestine (Itoh et al, 2001;Kumar et al, 1997), kidney (Birn et al, 2005), placenta (Bisseling et al, 2004), pancreas (Nabokina et al, 2004) and cell lines derived from various species (human and rabbit), the process of intracellular trafficking in the retina has not been clearly delineated. Recent report by Yoo and Park (2004) suggested that folate-receptor-targeted doxorubicin nano-aggregrates could be a potentially useful delivery system for folate-receptor-positive cells.…”