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Changes in aquaporin-4 and Kir4.1 expression in rats with inherited retinal dystrophy
S Lassiale1, F Valamanesh2, C Klein3
1INSERM U1138 - Equipe 17: De la Physiopathologie des maladies rétiniennes aux Avancées Cliniques, Université Pierre et Marie Curie Paris VI, Université Paris-Descartes- Sorbonne, Paris Cité, Centre de Recherches des Cordeliers, 15, rue de l'Ecole de Médecine, 75006, Paris, France.
Abstract:
Muller glial cells (MGC) are essential for normal functioning of retina. They are especially involved in potassium (K+) and water homeostasis, via inwardly rectifying K+ (Kir 4.1) and aquaporin-4 (AQP4) channels respectively. Because MGC appear morphologically and functionally altered in most retinal pathologies, we studied the expression of AQP 4 and Kir 4.1 during the time course of progressive retinal degeneration in Royal College of Surgeons (RCS) rats, an animal model for the hereditary human retinal degenerative disease Retinitis pigmentosa. Simultaneous detection of AQP4 and Kir 4.1 was performed by quantitative real-time polymerase chain reaction (QRT-PCR), Western blot and immunohistochemistry at birth and during progression of the pathology. Although small quantities of AQP4 and Kir 4.1 mRNA were detected at birth (postnatal day (PNd) 0) in both control and dystrophic rat retinas, proteins could not be detected at this age. Detectable proteins appeared in the second week of postnatal life. From PNd15 onwards, the time course in the expression of both AQP4 and Kir 4.1 mRNAs and protein was similar in dystrophic and control rats, with a progressive increase peaking at PNd60 and a subsequent decrease by one year. AQP4 protein and mRNA content were significantly lowered in dystrophic compared to control rats. Kir 4.1 protein levels were also lower in dystrophic retinas, while mRNA concentrations were unchanged and/or slightly higher in dystrophic rats. The discrepancies between Kir4.1 mRNA and protein suggest perturbation in protein translation due to the pathology. AQP4 and Kir 4.1/vimentin co-immunolabeling showed that: 1) apical radial processes of some MGC invaded the subretinal zone, and 2) MGC morphology was distorted in advanced pathology. MGC became hypertrophic both during the pathology and also with age in control rats. In conclusion, our results confirm that this inherited photoreceptor degeneration also leads to progressive alterations in physiological and morphological parameters of MGC which may aggravate retinal impairment.
Insights
Muller glial cells (MGC) show altered expression of aquaporin-4 (AQP4) and Kir 4.1 channels in progressive retinal degeneration. These changes in MGC function and morphology may worsen vision loss in retinitis pigmentosa.
Area of Science:
- Neuroscience
- Ophthalmology
- Cell Biology
Background:
- Muller glial cells (MGC) are crucial for retinal function, maintaining potassium and water homeostasis through aquaporin-4 (AQP4) and Kir 4.1 channels.
- MGC are known to be altered in retinal pathologies, including retinitis pigmentosa.
Purpose of the Study:
- To investigate the expression of AQP4 and Kir 4.1 in Muller glial cells during progressive retinal degeneration.
- To analyze changes in MGC morphology and function in Royal College of Surgeons (RCS) rats, an animal model for retinitis pigmentosa.
Main Methods:
- Quantitative real-time polymerase chain reaction (QRT-PCR) to measure mRNA levels of AQP4 and Kir 4.1.
- Western blot and immunohistochemistry to detect protein expression and localization of AQP4 and Kir 4.1.
- Analysis performed at various time points from birth to one year in control and RCS rats.
Main Results:
- AQP4 protein and mRNA levels were significantly reduced in dystrophic RCS rat retinas compared to controls.
- Kir 4.1 protein levels were lower in dystrophic retinas, while mRNA levels remained unchanged or slightly increased, suggesting translational dysregulation.
- MGC exhibited distorted morphology and hypertrophy, with apical processes invading the subretinal space in advanced stages of degeneration.
Conclusions:
- Progressive photoreceptor degeneration in RCS rats leads to significant alterations in MGC expression of AQP4 and Kir 4.1.
- These physiological and morphological MGC changes may contribute to the exacerbation of retinal impairment in retinitis pigmentosa.
- The study highlights the critical role of MGC in maintaining retinal integrity and the detrimental impact of their dysfunction in inherited retinal diseases.
