Research reportATP-sensitive potassium channels (KATP) in retina: a key role for delayed ischemic tolerance
Introduction
Ischemic preconditioning (IPC) is a powerful protective mechanism against ischemic injury that has been shown to occur in a variety of organ systems, including heart, brain, spinal cord, liver, lung, skeletal muscle and recently, retina [9], [21], [29], [35], [42]. Ischemic preconditioning has both immediate and delayed protective effects, the importance of which varies between species and organ systems. While the exact mechanisms of both protective components are yet to be clearly defined, ischemic preconditioning is a multifactorial process requiring the interaction of numerous signals, second messengers and effector mechanisms.
ATP-sensitive potassium channels (KATP channels) couple cell metabolism to membrane potential in many organs [3]. The pancreatic-cell KATP channels play a critical role in the regulation of glucose-stimulated insulin secretion [7], [12]. KATP channels shorten the action potential in hypoxic cardiac muscle and provide one pathway for vasodilatation in vascular smooth muscle [13], [14], [16], [39]. They are also characterized by their inhibition by antidiabetic sulfonylurea drugs such as glibenclamide, glipizide, tolbutamide [16], [45] and their activation by K+ channel openers (KCOs) such as (−)cromakalim, pinacidil, diazoxide [13], [14], [39]. Although the role of KATP channels in the mechanism of myocardial IPC is still controversial depending on the species (for review see Ref. [36]), a considerable body of evidence has implicated KATP channels in cerebral protection. Opening of KATP channels with KCOs protect neurons against the deleterious effects of excitotoxicity and ischemia [1], [22]. Recently, KATP channels have also been shown to be involved in epileptic and ischemic brain tolerance [23], [38]. KATP channels are made of a complex of two structurally distinct subunits, an inwardly rectifying potassium channel subunit (Kir6.x) forming the channel pore [26] and a regulatory subunit, the sulphonylurea receptor (SUR) belonging to the ATP-binding cassette superfamily [2], [25], [27]. A total of five isoforms of SURs have been cloned, SUR1 and four spliced variants of SUR2, SUR2A–D. Probably because the expression and distribution of KATP channels in retinal cells are not yet known, their physiological function in retina is still not well understood.
The aims of the present work were to determine the localization of KATP channels in normal retina and evaluate their potential roles in ischemic preconditioning in a rat model of ischemia induced by increased intraocular pressure (IOP).
Section snippets
Animals
Adult male Brown Norway rats weighing 250 g (Charles River Breeding Laboratory, St Aubain les Elbeuf, France) were housed in clear plastic cages in a room with controlled temperature (22±1°C) and a fixed 50-lx fluorescent (Philips, France) lighting schedule (lights on from 08:00 to 20:00 h). Food and tap water were provided ad libitum. Rats were acclimated for 1 week before experiments. Before electroretinogram (ERG) recordings, the animals were kept in total darkness for a minimum of 16 h.
Distribution of KATP channels in retina
The sensitive reverse transcription-PCR (Fig. 2A) shows that SUR1 and KIR6.2 were detected in retina, whereas the expression of SUR2 was not detectable. In situ hybridization analysis confirms this result. As shown in Fig. 2C, Kir6.2 is highly expressed in retinal pigment epithelium, inner segments of photoreceptors, outer plexiform, inner nuclear and ganglion cell layers, and probably Müller cells. The SUR1 mRNA hybridization is predominantly confined to retinal pigment epithelium, inner
Discussion
Four major findings emerge from the present experiments: (i) the sulphonylurea receptor SUR1 and the inward-rectifier K+ channel subunit Kir6.2 are highly expressed in the control retina; (ii) as previously described in a model of retinal ischemia induced by optic nerve bundle ligation [42], ischemic preconditioning induces impressive retinal tolerance to ischemia in a model of increased intraocular pressure; (iii) the mechanism of the retinal tolerance involves the early activation of KATP
Acknowledgements
This work was supported by the Centre National de la Recherche Scientifique (CNRS), the Association pour la Recherche sur le Cancer (ARC), the Conseil Regional (PACA), the Association Française contre la Myopathie (AFM) and the Fondation de l’Avenir. We thank C. Widmann, N. Vaillant, G. Jarretou, F. Aguila and V. Lopez for technical assistance.
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