Importantly PRL is proteolytically cleaved in

Importantly, PRL is proteolytically cleaved in the retina to yield vasoinhibins (Clapp et al., 2006), a family of peptides that act on both endothelial and RPE myeloperoxidase to prevent the hypervasopermeability associated with diabetes (Arredondo Zamarripa et al., 2014). Vasoinhibins exert actions through a mechanism independent of the PRL receptor (Bajou et al., 2014). The existence of such mechanisms therefore makes the prlr−/− mouse a complex model since exaggerated signaling through non-PRL receptor pathways may be expected. However, we previously demonstrated that in spite of being hyperprolactinemic, prlr−/− mice do not show increased levels of vasoinhibins in their retinas (Arnold et al., 2010). Our general view is that antiapoptotic mechanisms including the PRL signaling pathway degrade with advancing age so that RPE cells become vulnerable to normal proapoptotic stressors such as ROS, SIRT2, and elevated intracellular Ca2+ levels, creating a tipping point beyond which retinal homeostasis is lost (Fig. 7), leading to visual dysfunction as we previously reported (Arnold et al., 2014). Concomitantly with RPE damage, rhodopsin mRNA levels and cone and rod photoreception are compromised in the prlr−/− mice (Arnold et al., 2014). A similar degree of alterations in electroretinogram parameters was previously shown to associate with reduced visual acuity in various animal models (Bonnet Wersinger et al., 2014; Deming et al., 2015; Hilgen et al., 2012; Kohl et al., 2015). Most studies devoted to detecting changes in plasma levels of PRL during aging in humans have been carried out in males, usually with age-range subject selection, which results in considerable variability and conflicting results. In most studies, healthy aging subjects showed no change in circulating levels of pituitary PRL (Rossmanith et al., 1992; Schiavi et al., 1992; Yamaji et al., 1976), while some showed a decrease (Saucedo et al., 2000; van Coevorden et al., 1991). From a clinical point of view, one may consider the option of increasing levels of systemic PRL during advancing age in order to protect the RPE. However, the potential undesirable effects of induced hyperprolactinemia prompt us to propose instead that targeting SIRT2 or TRPM2 channels with inhibitors may improve RPE function in conditions that induce oxidative stress in the RPE. Therapeutic interventions may also benefit from identifying the signal transduction pathways that link PRL receptor stimulation to antioxidant actions. STAT3 appears to be a main candidate since signaling through the PRL receptor canonically involves JAK2/STAT3 activation (Bole-Feysot et al., 1998), and neuronal oxidative stress associates with reduced JAK2/STAT signaling (Kaur et al., 2005; Monroe and Halvorsen, 2006a), an effect that can be counteracted by anti-oxidant molecules including GSH and NAC (). In particular, knockdown of STAT3 has been recently shown to abolish the protective effects of innate immune system activation in the retina during oxidative stress (Patel and Hackam, 2014), and PRL is a well-known modulator of this system (Díaz et al., 2013).
Author Contributions
Conflict of Interest Statement
Acknowledgements We would like to thank M. Diaz Muñoz and M. Flourakis for insights. R. Meléndez García, D. Arredondo Zamarripa, E. Arnold, X. Ruiz-Herrera, G. Baeza Cruz, and N. Adán are Master\'s and Doctoral students from Programa de Posgrado en Ciencias, Universidad Nacional Autónoma de México (UNAM) and received fellowships from CONACYT. We thank F. López-Barrera, G. Nava, D. Mondragón, A. Prado, M. García, and E. N. Hernández Ríos for their technical assistance, and D. D. Pless for critically editing the manuscript. This study was supported by the UNAM grant IN201814 (ST), the National Council of Science and Technology of Mexico (CONACYT) grant 176393 (ST), and the Shedid grant (ATM). The role of the three funders strictly consisted in providing funds to purchase all materials necessary in this study.