Hong Yu Ah, Yang Keum Jin, Jung So Young, Park Ki Cheol, Choi Hyunsu, Oh Jeong Min, Lee Sang Ju, Chang Yoon Kyung, Park Cheol Whee, Yang Chul Woo, Kim Suk Young, Hwang Hyeon Seok
Division of Nephrology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Clinical Research Institute, Daejeon St. Mary's Hospital, Daejeon, Republic of Korea.
Oxid Med Cell Longev. 2017;2017:5031926. doi: 10.1155/2017/5031926. Epub 2017 Mar 29.
The protective mechanism of paricalcitol remains unclear in renal ischemia-reperfusion (IR) injury. We investigated the renoprotective effects of paricalcitol in IR injury through the prostaglandin E (PGE) receptor EP4. Paricalcitol was injected into IR-exposed HK-2 cells and mice subjected to bilateral kidney ischemia for 23 min and reperfusion for 24 hr. Paricalcitol prevented IR-induced cell death and EP4 antagonist cotreatment offset these protective effects. Paricalcitol increased phosphorylation of Akt and cyclic AMP responsive element binding protein (CREB) and suppressed nuclear factor-B (NF-B) in IR-exposed cells and cotreatment of EP4 antagonist or EP4 small interfering RNA blunted these signals. In vivo studies showed that paricalcitol improved renal dysfunction and tubular necrosis after IR injury and cotreatment with EP4 antagonist inhibited the protective effects of paricalcitol. Phosphorylation of Akt was increased and nuclear translocation of p65 NF-B was decreased in paricalcitol-treated mice with IR injury, which was reversed by EP4 blockade. Paricalcitol decreased oxidative stress and apoptosis in renal IR injury. Paricalcitol also attenuated the infiltration of inflammatory cells and production of proinflammatory cytokines after IR injury. EP4 antagonist abolished these antioxidant, anti-inflammatory, and antiapoptotic effects. The EP4 plays a pivotal role in the protective effects of paricalcitol in renal IR injury.
帕立骨化醇在肾缺血再灌注（IR）损伤中的保护机制尚不清楚。我们通过前列腺素E（PGE）受体EP4研究了帕立骨化醇在IR损伤中的肾脏保护作用。将帕立骨化醇注射到暴露于IR的HK-2细胞以及双侧肾脏缺血23分钟并再灌注24小时的小鼠体内。帕立骨化醇可预防IR诱导的细胞死亡，而EP4拮抗剂共同处理可抵消这些保护作用。帕立骨化醇可增加IR暴露细胞中Akt和环磷酸腺苷反应元件结合蛋白（CREB）的磷酸化，并抑制核因子-κB（NF-κB），而EP4拮抗剂或EP4小干扰RNA的共同处理可减弱这些信号。体内研究表明，帕立骨化醇可改善IR损伤后的肾功能障碍和肾小管坏死，而与EP4拮抗剂共同处理可抑制帕立骨化醇的保护作用。在接受IR损伤的帕立骨化醇治疗的小鼠中，Akt的磷酸化增加，p65 NF-κB的核转位减少，而EP4阻断可逆转这种情况。帕立骨化醇可降低肾IR损伤中的氧化应激和细胞凋亡。帕立骨化醇还可减轻IR损伤后炎症细胞的浸润和促炎细胞因子的产生。EP4拮抗剂消除了这些抗氧化、抗炎和抗凋亡作用。EP4在帕立骨化醇对肾IR损伤的保护作用中起关键作用。
