UV-induced DNA Damage in Skin is Reduced by CaSR Inhibition

The epidermis maintains a cellular calcium gradient that supports keratinocyte differentiation from its basal layers (low) to outer layers (high) leading to the development of the stratum corneum, which resists penetration of UV radiation. The calcium-sensing receptor (CaSR) expressed in keratinocytes responds to the calcium gradient with signals that promote differentiation. In this study, we investigated whether the CaSR is involved more directly in protection from UV damage in studies of human keratinocytes in primary culture and in mouse skin studied in vivo. siRNA-directed reductions in CaSR protein levels in human keratinocytes significantly reduced UV-induced direct cyclobutane pyrimidine dimers (CPD) by ~80% and oxidative DNA damage (8-OHdG) by ~65% compared with control transfected cells. Similarly, in untransfected cells, the CaSR negative modulator, NPS-2143 (500 nm), reduced UV-induced CPD and 8-OHdG by ~70%. NPS-2143 also enhanced DNA repair and reduced Reactive Oxygen Species (ROS) by ~35% in UV-exposed keratinocytes, consistent with reduced DNA damage after UV exposure. Topical application of NPS-2143 also protected hairless Skh:hr1 mice from UV-induced CPD, oxidative DNA damage and inflammation, similar to the reductions observed in response to the well-known photoprotection agent 1,25(OH)₂ D₃ (calcitriol). Thus, negative modulators of the CaSR offer a new approach to reducing UV-induced skin damage.