P2X7 and A 2A receptor endogenous activation protects against neuronal death caused by CoCl 2 ‐induced photoreceptor toxicity in the zebrafish retina

PISERA?FUSTER, ANTONELLA; MEDRANO, MATÍAS P.; FAILLACE, MARÍA PAULA; MEDRANO, MATÍAS P.; FAILLACE, MARÍA PAULA; BERNABEU, RAMÓN O.; BERNABEU, RAMÓN O.; PISERA?FUSTER, ANTONELLA

JOURNAL OF COMPARATIVE NEUROLOGY

WILEY-LISS, DIV JOHN WILEY & SONS INC

Año: 2020 vol. 528 p. 2000 - 2020

0021-9967

Injured retinas in mammals do not regenerate and heal with loss of function. The adult retina of zebrafish self-repairs after damage by activating cell-intrinsic mechanisms, which are regulated by extrinsic signal interactions. Among relevant regulatory extrinsic systems, purinergic signalling regulates progenitor proliferation during retinogenesis and regeneration and glia proliferation in proliferative retinopathies. ATP-activated P2X7 (P2RX7) and adenosine (P1R) receptors are involved in the progression of almost all retinopathies leading to blindness. Here, we examined P2RX7 and P1R participation in the retina regenerative response induced by photoreceptor damage caused by a specific dose of CoCl2. First, we found that treatment of uninjured retinas with a potent agonist of P2RX7 (BzATP) provoked photoreceptor damage and mitotic activation of multipotent progenitors. In CoCl2-injured retinas, blockade of endogenous extracellular ATP activity on P2RX7caused further neurodegeneration, Müller cell gliosis, progenitor proliferation and microgliareactivity. P2RX7 inhibition in injured retinas also increased the expression of lin28a and tnfα genes, which are related to multipotent progenitor proliferation. Levels of hif1α, vegf3r and vegfaa mRNA were enhanced by blockade of P2RX7 immediately after injury, indicating hypoxic like damage and endothelial cell growth and proliferation. Complete depletion of extracellular nucleotides with an apyrase treatment strongly potentiated cell death and progenitor proliferation induced with CoCl2. Blockade of adenosine P1 and A2A receptors (A2AR) had deleterious effects and deregulated normal timing for progenitor and precursor cell proliferation following photoreceptor damage. ATP via P2RX7 and adenosine via A2AR are survival extracellular signals key for retina regeneration in zebrafish.