Lactate Transport and Receptor Actions in Retina: Potential Roles in Retinal Function and Disease

Kolko, Miriam; Vosborg, Fia; Henriksen, Ulla; Hasan‐Olive, Mahdi; Diget, Elisabeth Holm; Vohra, Rupali; Gurubaran, Iswariya Raja Sridevi; Gjedde, Albert; Mariga, Shelton T.; Skytt, Dorte M.; Utheim, Tor Paaske; Storm‐Mathisen, Jon; Bergersen, Linda Hildegard

doi:10.1007/s11064-015-1792-x

Cited by 42 publications

(43 citation statements)

References 76 publications

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“…12,13 However, in the early 2000s a new target for lactate was discovered, namely the receptor GPR81. Abundant GPR81 expression was recently identified the inner retina, 20 indicating that activation of GPR81 may play a prominent role in inner retinal homeostasis. Thus, we aimed to elucidate whether the lactate-linked protective effects on Müller cells were due to direct metabolism of L-lactate and/or activation through GPR81.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, mRNA expression levels of GPR81 have also been quantified in retinas obtained from mice. 20 However, in this study, we aimed to verify the presence of the receptor and possible regulations in response to altered levels of energy availability. Deprivation of glucose led to increased GPR81 expression, indicating an amplification of lactate-mediated effects through GPR81 activation.…”

Section: Discussionmentioning

confidence: 99%

“…19 The presence of lactate receptor GPR81 was recently revealed in high abundance in the retina, especially in RGCs and Müller cells. 20 Thus, it is tempting to suggest that lactatemediated protection occurs through the activation of GPR81.…”

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confidence: 99%

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Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Vohra

Aldana

Bergersen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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Citation: Vohra R, Aldana BI, Waagepetersen H, Bergersen LH, Kolko M. Dual properties of lactate in Müller cells: the effect of GPR81 activation. Invest Ophthalmol Vis Sci. 2019;60:999-1008. https://doi.org/ 10.1167/iovs.18-25458PURPOSE. Besides being actively metabolized, lactate may also function as a signaling molecule by activation of the G-protein-coupled receptor 81 (GPR81). Thus, we aimed to characterize the metabolic effects of GPR81 activation in Müller cells.METHOD. Primary Müller cells from mice were treated with and without 10 mM L-lactate in the presence or absence of 6 mM glucose. The effects of lactate receptor GPR81 activation were evaluated by the addition of 5 mM 3,5-DHBA (3,5-dihydroxybenzoic acid), a GPR81 agonist. Western blot analyses were used to determine protein expression of GPR81. Cell survival was assessed through 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) viability assays. Lactate release was quantified by commercially available lactate kits. 13 Clabeling studies via mass spectroscopy and Seahorse analyses were performed to evaluate metabolism of lactate and glucose, and mitochondrial function. Finally, Müller cell function was evaluated by measuring glutamate uptake.RESULTS. The lactate receptor, GPR81, was upregulated during glucose deprivation. Treatment with a GPR81 agonist did not affect Müller cell survival. However, GPR81 activation diminished lactate release allowing lactate to be metabolized intracellularly. Furthermore, GPR81 activation increased metabolism of glucose and mitochondrial function. Finally, maximal glutamate uptake decreased in response to GPR81 activation during glucose deprivation.CONCLUSIONS. The present study revealed dual properties of lactate via functioning as an active metabolic energy substrate and a regulatory molecule by activation of the GPR81 receptor in primary Müller cells. Thus, combinational therapy of lactate and GPR81 agonists may be of future interest in maintaining Müller cell survival, ultimately leading to increased resistance toward retinal neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Dual Properties of Lactate in Müller Cells: The Effect of GPR81 Activation

Vohra

Aldana

Bergersen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Moreover, recent studies have suggested a neuroprotective role of lactate in the retina (Kolko et al. ; Vohra & Kolko ; Vohra et al. ).…”

Section: Introductionmentioning

confidence: 99%

Potential metabolic markers in glaucoma and their regulation in response to hypoxia

Vohra

Dalgaard

Vibæk

et al. 2019

Acta Ophthalmologica

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Purpose: To assess novel differences in serum levels of glucose, lactate and amino acids in patients with normal-tension glaucoma (NTG) compared to agematched controls, at baseline and in response to universal hypoxia. Methods: Twelve patients diagnosed with NTG and eleven control subjects underwent normobaric hypoxia for 2 hr. Peripheral venous blood samples were taken at baseline, during hypoxia and in the recovery phase. Serum glucose and lactate levels were measured by a blood gas analyser. Amino acids were analysed by high-performance liquid chromatography. Results: Baseline levels of lactate and total amino acids were significantly lower in patients with NTG compared to healthy controls. No differences were seen in blood glucose levels between the two groups. Lactate levels remained unchanged during hypoxia in the control group, but increased in patients with NTG. In the recovery phase, total amino acid levels were reduced in the control group, whereas no changes were found in patients with NTG. Conclusion: Reduced serum levels of lactate and total amino acids were identified as potential markers for NTG. Moreover, significant differential regulatory patterns of certain amino acids were found in patients with NTG compared to control subjects. Overall, our results suggest a link between systemic energy metabolites and NTG and support a novel understanding of glaucoma as an inner retinal manifestation of a systemic condition.

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“…GPR81 is expressed at much lower levels in the brain, where it seems to be involved in neuronal signalling, as well as the retina where it has been implicated in regulation of blood flow to meet metabolic demands (17)(18)(19)(20). It is also induced in several cancer types where it appears to play a role in the adaptation to the ischemic tumor microenvironment (21).…”

Section: Introductionmentioning

confidence: 99%