Abstract
Purpose: :
Retinal cells use monocarboxylates (e.g. lactate) as energy substrates. Retinal supply of monocarboxylates depends on the activity of specific transporters. Recently, we showed that SMCT1, a Na+-coupled monocarboxylate transporter, is expressed in retinal neurons and RPE. The expression in RPE is restricted to the basal membrane. Two other monocarboxylate transporters that are H+-coupled are also expressed in RPE (MCT1 in apical membrane and MCT3 in basal membrane). Here we examined the effects of the NSAID diclofenac on SMCT1 and MCT1/MCT3 in RPE.
Methods: :
The influence of diclofenac on SMCT1 activity was tested in two different heterologous expression systems: a mammalian cell expression system and the Xenopus laevis oocyte expression system. Uptake assays were used to examine the effects of diclofenac on constitutively expressed SMCT1 in ARPE-19 (RPE) and RGC5 (ganglion) cells and on MCT1/MCT3 in ARPE-19 cells.
Results: :
SMCT1 expressed heterologously in HRPE cells was stimulated 2- to 5-fold by diclofenac; but no stimulatory effect was observed in Xenopus oocytes. The cell-type specificity of the diclofenac effect was tested using MCF-7 (mammary epithelial) cells and ARPE-19 cells. Stimulatory effects of diclofenac were observed only in RPE cell lines (HRPE and ARPE-19). Similarly, no effect of diclofenac was observed on SMCT1 constitutively expressed in RGC5 cells. However, diclofenac had a marked stimulatory effect on MCT1/MCT3 in ARPE-19 cells. This stimulation increased further in the presence of an MCT1 inhibitor.
Conclusions: :
We reported recently that several NSAIDs inhibit SMCT1. Here we show that diclofenac, also a NSAID, does not inhibit, but instead stimulates SMCT1. This effect is specific to RPE. Diclofenac is also a stimulator of MCT1/MCT3. NSAIDs are increasingly used for treatment of retinal diseases such as diabetic retinopathy and macular edema. Our studies show that different NSAIDs are likely to have different effects on the retinal supply of monocarboxylates through their differential effects on SMCT1 and MCT1/MCT3.
Keywords: retinal pigment epithelium • retina