Retinal transfer of nicotinate by H+-monocarboxylate transporter at the inner blood-retinal barrier

Abstract

Nicotinic acid is a constituent of the coenzymes NAD and NADP. It also serves as an agonist for the G-protein-coupled receptor GPR109A. Nicotinic acid is widely used at high doses as a lipid-lowering drug, which is associated with an ocular side effect known as niacin maculopathy. Here we investigated the mechanism by which nicotinate is transferred into retina across the inner blood-retinal barrier (BRB). In vivo the blood-to-retina transport of [3H]-nicotinate was studied using the carotid artery injection technique. The characteristics of nicotinate transport at the inner BRB were examined in a conditionally immortalized rat retinal capillary endothelial cell line (TR-iBRB2), an in vitro model of inner BRB. The expression of transporters in TR-iBRB2 cells was determined by reverse transcription-polymerase chain reaction. In vivo [3H]-nicotinate uptake by the retina was 5.4-fold greater than that of [14C]-sucrose, a BRB impermeable vascular space marker. Excess amounts of unlabeled nicotinate and salicylate significantly decreased the in vivo retinal uptake of [3H]-nicotinate. [3H]-Nicotinate was taken up by TR-iBRB2 cells via an H+-dependent saturable process with a Michaelis constant of ~7 mM. Na+ had minimal effect on the uptake. The H+-dependent uptake was significantly inhibited by endogenous monocarboxylates such as lactate and puruvate, and monocarboxylic drugs such as valproate, salicylate, and ibuprofen. These characteristics are consistent with those of H+-coupled monocarboxylate transporters (MCTs). MCT1, MCT2, and MCT4 mRNAs were expressed in TR-iBRB2 cells. The Na+-dependent monocarboxylate transporters SMCT1 and SMCT2 were not expressed in these cells. In conclusion, transfer of nicotinate from blood to retina across the inner BRB occurs primarily via H+-coupled monocarbxylate transporters.

Nicotinic Acid Activates the Capsaicin Receptor TRPV1

“…Transporters for nicotinic acid have been functionally identified, however, their molecular identify remain unknown 38-40 . As has been previously proposed, the ubiquitous H + -coupled monocarboxylate transporters and Na + -coupled monocarboxylate transporters are very interesting potential candidates underlying nicotinic acid transportation 39, 44-46 . Monocarboxylate transporters are known to transport L-lactate, pyruvate, the ketone bodies and many other monocarboxylates across the plasma membrane 47 .…”

NAD+ maintenance attenuates light induced photoreceptor degeneration

“…Direct administration of NAD + has been shown to be beneficial in traumatic brain injury-induced neuron death (Won et al, 2012), brain ischemia (Zheng et al, 2012), and tumor necrosis factor-induced optic neuropathy (Kitaoka et al, 2009). The circulating blood supply of nicotinate crosses the blood-retinal barrier (BRB) through H + -monocarboxylate transporter (Tachikawa et al, 2011). These data make nicotinamide or NAD + promising therapeutics in treating retinal or brain neurodegenerative diseases.…”

Constitutive Expression of HCA2in Human Retina and Primary Human Retinal Pigment Epithelial Cells

“…[34][35][36] Niacin maculopathy is an abnormal accumulation of niacin in the retina. Tachikawa et al 37 have shown that niacin may enter the retina via an Hþ-coupled monocarboxylate transporter at the blood-retina barrier formed by the tight junctions of retinal capillary endothelial cells and RPE. Whether or not HCA 2 plays a role in the pathogenesis of niacin maculopathy requires further investigation.…”