Renal Reabsorption of Folates: Pharmacological and Toxicological Snapshots

Abstract

Folates are water-soluble B9 vitamins that serve as one-carbon donors in the de novo synthesis of thymidylate and purines, and in the conversion of homocysteine to methionine. Due to their key roles in nucleic acid synthesis and in DNA methylation, inhibiting the folate pathway is still one of the most efficient approaches for the treatment of several tumors. Methotrexate and pemetrexed are the most prescribed antifolates and are mainly used in the treatment of acute myeloid leukemia, osteosarcoma, and lung cancers. Normal levels of folates in the blood are maintained not only by proper dietary intake and intestinal absorption, but also by an efficient renal reabsorption that seems to be primarily mediated by the glycosylphosphatidylinositol- (GPI) anchored protein folate receptor α (FRα), which is highly expressed at the brush-border membrane of proximal tubule cells. Folate deficiency due to malnutrition, impaired intestinal absorption or increased urinary elimination is associated with severe hematological and neurological deficits. This review describes the role of the kidneys in folate homeostasis, the molecular basis of folate handling by the kidneys, and the use of high dose folic acid as a model of acute kidney injury. Finally, we provide an overview on the development of folate-based compounds and their possible therapeutic potential and toxicological ramifications.

Keywords: acute kidney injury; folate; folate receptor; folic acid; nephrotoxicity; renal reabsorption.

Figure 1

Renal reabsorption of folates from glomerular filtrate in the proximal tubules under physiological conditions is postulated to mainly rely on the high-affinity folate receptor FRα through a process of transcytosis to the basolateral membrane into the blood. Possible roles of megalin, which binds soluble folate binding proteins (FBP), and cubilin, which binds albumin (ALB), for uptake of folates under conditions of folate deficiency over additional endocytic mechanisms has also been proposed. The folate-specific transporters reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) are highly expressed in the proximal tubule, with known expression of RFC at the basolateral membrane and unknown location and function of PCFT in the context of renal folate transport. Additional low-affinity, high-capacity folate transporters expressed at the apical membrane include the multidrug resistance-associated proteins (MRPs) efflux pumps 2 and 4 and the organic anion transporters (OAT) K1, K2, and 4. At the basolateral membrane, OAT1, 2, and 3 as well as the efflux pump MRP3 may likewise contribute to renal folate transport and general folate homeostasis.

Figure 2

Vintafolide (EC145). The chemical structure was generated using the open access software Chemspider (http://www.chemspider.com/). Vintafolide structure was downloaded from the DrugBank (https://www.drugbank.ca/drugs/DB05168).