The renal transport protein OATP4C1 mediates uptake of the uremic toxin asymmetric dimethylarginine (ADMA) and efflux of cardioprotective L-homoarginine

Abstract

Elevated plasma concentrations of the uremic toxin asymmetrical dimethylarginine (ADMA) and low plasma concentrations of L-homoarginine are independently associated with cardiovascular events and total mortality. Enzymes degrading ADMA [dimethylaminohydrolase 1 (DDAH1)] and synthesizing L-homoarginine [L-arginine:glycine amidinotransferase (AGAT)] are expressed in human proximal tubule cells. So far, it is not known which transport protein in the basolateral membrane of proximal tubule cells is mediating the uptake of ADMA into the cells for subsequent degradation or the export of intracellularly synthesized L-homoarginine. One study suggested that the uptake transporter OATP4C1 (gene symbol SLCO4C1) may be involved in the transport of ADMA and other uremic toxins. OATP4C1 is a member of the SLCO/SLC21 family of solute carriers, localized in the basolateral membrane of human proximal tubule cells. By using stably-transfected HEK cells overexpressing human OATP4C1, we demonstrate that ADMA and L-homoarginine are substrates of OATP4C1 with Km values of 232.1 μM and 49.9 μM, respectively. ADMA and the structurally related uremic toxin SDMA (100 μM) inhibited OATP4C1-mediated L-homoarginine uptake (P < 0.01), whereas other tested uremic toxins such as urea and p-cresyl sulfate have no effect on OATP4C1-mediated transport. Preloading experiments (300 μM for 60 min) with subsequent efflux studies revealed that OATP4C1 also facilitates efflux e.g. of L-homoarginine. Both ADMA and L-homoarginine are substrates of human OATP4C1. Because proximal tubule cells are one site of ADMA metabolism and L-homoarginine synthesis, we postulate a protective role of OATP4C1 by mediating uptake of ADMA from and export of L-homoarginine into the systemic circulation.

Vectorial transport of the arginine derivatives asymmetric dimethylarginine (ADMA) and l-homoarginine by OATP4C1 and P-glycoprotein studied in double-transfected MDCK cells

“…2c, d). In line with published data for OATP4C1 (Taghikhani 2019;Mikkaichi et al 2004;Shirasaka 2009), a band with a molecular weight of 115 kDa was detected in the MDCK-OATP4C1 single-transfected as well as in the MDCK-OATP4C1-P-gp double-transfected cell line (Fig. 2c).…”

“…Cloning of the human SLCO4C1 cDNA encoding human OATP4C1 and establishment of the expression vector pOATP4C1.31 has been described recently (Taghikhani et al 2019 ). Generation of MDCK-VC and MDCK-OATP4C1 cells was conducted according to previously published protocols (Misaka et al 2016 ; Taghikhani et al 2017 ).…”

“…Recently, we could demonstrate that both ADMA and l -homoarginine are substrates of OATP4C1. Furthermore, this transport protein is also capable of exporting ADMA and l -homoarginine out of cells (Taghikhani et al 2019 ). Considering ADMA, these findings are in line with an animal study conducted by Toyohara et al, which investigated the effects of OATP4C1 overexpression on general cardiovascular outcome and uremic toxin plasma concentrations in the state of renal insufficiency (Toyohara et al 2009 ).…”

Knockdown of SLCO4C1 inhibits cell proliferation and metastasis in endometrial cancer through inactivating the PI3K/Akt signaling pathway

“…According to the TCGA database and GO analysis, 57 DEGs were revealed to be associated with the survival time and clinical stage of tumor patients, and SLCO4C1 was revealed to be involved in cell differentiation and the composition of the cell membrane. Moreover, it has been reported in literature to be closely correlated with kidney disease, head and neck cancer and reproductive development (9)(10)(11)(12)(13). Therefore, the association of SLCO4C1 with EC was specifically investigated in the present study.…”

“…According to The Cancer Genome Atlas (TCGA) datasets, solute carrier organic anion transporter family member 4C1 (SLCO4C1) upregulation was revealed to be strongly associated with the survival time and clinical stage of patients with EC. SLCO4C1 is a human kidney-specific organic anion transporting polypeptide (9,10). In addition, SLCO4C1 was revealed to excrete uremic toxins, which led to reduced blood pressure and decreased kidney inflammation (11,12).…”