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Osmotic expression of aldose reductase in retinal pigment epithelial cells: involvement of NFAT5

  • Basic Science
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Abstract

Background

Diabetic retinopathy is associated with osmotic stress resulting from hyperglycemia and intracellular sorbitol accumulation. Systemic hypertension is a risk factor of diabetic retinopathy. High intake of dietary salt increases extracellular osmolarity resulting in systemic hypertension. We determined the effects of extracellular hyperosmolarity, chemical hypoxia, and oxidative stress on the gene expression of enzymes involved in sorbitol production and conversion in cultured human retinal pigment epithelial (RPE) cells.

Methods

Alterations in the expression of aldose reductase (AR) and sorbitol dehydrogenase (SDH) genes were examined with real-time RT-PCR. Protein levels were determined with Western blot analysis. Nuclear factor of activated T cell 5 (NFAT5) was knocked down with siRNA.

Results

AR gene expression in RPE cells was increased by high (25 mM) extracellular glucose, CoCl2 (150 μM)-induced chemical hypoxia, H2O2 (20 μM)-induced oxidative stress, and extracellular hyperosmolarity induced by addition of NaCl or sucrose. Extracellular hyperosmolarity (but not hypoxia) also increased AR protein level. SDH gene expression was increased by hypoxia and oxidative stress, but not extracellular hyperosmolarity. Hyperosmolarity and hypoxia did not alter the SDH protein level. The hyperosmotic AR gene expression was dependent on activation of metalloproteinases, autocrine/paracrine TGF-β signaling, activation of p38 MAPK, ERK1/2, and PI3K signal transduction pathways, and the transcriptional activity of NFAT5. Knockdown of NAFT5 or inhibition of AR decreased the cell viability under hyperosmotic (but not hypoxic) conditions and aggravated the hyperosmotic inhibition of cell proliferation.

Conclusions

The data suggest that sorbitol accumulation in RPE cells occurs under hyperosmotic, but not hypoxic and oxidative stress conditions. NFAT5- and AR-mediated sorbitol accumulation may protect RPE cells under conditions of osmotic stress.

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Authors and Affiliations

  1. Department of Ophthalmology and Eye Hospital, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, D-04103, Leipzig, Germany

    Anica Winges, Tarcyane Barata Garcia, Philipp Prager, Peter Wiedemann, Leon Kohen, Andreas Bringmann & Margrit Hollborn

  2. Helios Klinikum Aue, Aue, Germany

    Leon Kohen

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  1. Anica Winges
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  2. Tarcyane Barata Garcia
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Correspondence to Margrit Hollborn.

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Funding

The Geschwister Freter Stiftung (Hannover, Germany) and the Deutsche Forschungsgemeinschaft provided financial support in the form of grants (KO 1547/7-1). The sponsors had no role in the design or conduct of this research.

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All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.

This article does not contain any studies with human participants or animals performed by any of the authors.

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Winges, A., Garcia, T.B., Prager, P. et al. Osmotic expression of aldose reductase in retinal pigment epithelial cells: involvement of NFAT5. Graefes Arch Clin Exp Ophthalmol 254, 2387–2400 (2016). https://doi.org/10.1007/s00417-016-3492-x

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  • DOI: https://doi.org/10.1007/s00417-016-3492-x

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