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Reticulated Retinoic Acid Synthesis is Implicated in the Pathogenesis of Dry Eye in Aqp5 Deficiency Mice
Huanhuan Ge1, Guohu Di1,2, Bin Li1
1School of Basic Medicine, Qingdao University, Qingdao, China.
Investigative Ophthalmology & Visual Science
|July 17, 2024
Summary
Aquaporin 5 (AQP5) deficiency impairs retinoic acid (RA) metabolism, worsening dry eye disease (DED). Restoring RA improves DED symptoms in AQP5-deficient models by regulating JunB and Aldh1a1.
Area of Science:
- Ocular surface disease research
- Corneal biology and physiology
- Molecular mechanisms of dry eye disease
Background:
- Aquaporins, particularly aquaporin 5 (AQP5), play crucial roles in maintaining ocular surface homeostasis.
- Dry eye disease (DED) is associated with complex pathological changes in the cornea, including alterations in cellular function and metabolism.
- Retinoic acid (RA) is a key regulator of corneal epithelial cell proliferation, differentiation, and apoptosis, and its metabolic dysregulation is linked to DED.
Purpose of the Study:
- To investigate the mechanisms underlying retinoic acid (RA) metabolic abnormalities in corneas lacking aquaporin 5 (AQP5).
- To elucidate the role of AQP5 in regulating RA metabolism and its contribution to the pathogenesis of dry eye disease (DED).
Main Methods:
- Induction of dry eye (DE) models using scopolamine hydrobromide and utilization of Aqp5 knockout (Aqp5-/-) mice.
- Assessment of corneal epithelial alterations, tear secretion, goblet cell counts, and corneal punctate defects.
- Investigation of AQP5's impact on RA-related enzymes and receptors in corneal epithelial cells (CECs) using pharmacological treatments and molecular assays (qRT-PCR, Western blot, ChIP-PCR, TUNEL).
Main Results:
- Reduced expression of AQP5 and Aldh1a1 was observed in corneal epithelial cells (CECs) of DE mice and in human corneal epithelial cells (HCECs) exposed to hyperosmotic stress.
- Aqp5-/- mice exhibited a dry eye phenotype with diminished Aldh1a1 levels.
- Retinoic acid (RA) treatment ameliorated the DE phenotype in Aqp5-/- mice by reducing apoptosis and promoting proliferation. ChIP-PCR confirmed JunB enrichment in the Aldh1a1 promoter, and inhibition of JunB (SR treatment) upregulated Aldh1a1 and promoted cell proliferation.
Conclusions:
- Downregulation of AQP5 expression and abnormal RA metabolism are key features of DED.
- AQP5 deficiency leads to reduced RA production via JunB activation, contributing to the development of DED symptoms.
- Targeting the AQP5-JunB-Aldh1a1 pathway may offer therapeutic strategies for managing DED.
