Abstract
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 E2 (PGE2) 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-κB (NF-κB) 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-κB 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.
Highlights
Renal ischemia-reperfusion (IR) injury is a major cause of acute kidney injury (AKI) [1, 2]
Paricalcitol did not affect the mRNA levels of prostaglandin E synthases (PGES), the enzyme that isomerizes the PGH2 to prostaglandin E2 (PGE2), or 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the enzyme that catalyzes conversion of PGE2 to a less bioactive form (Figure 1(b))
This study demonstrated that paricalcitol pretreatment had renoprotective effects in renal IR injury by upregulating the PGE2-EP4 signaling pathway
Summary
Renal ischemia-reperfusion (IR) injury is a major cause of acute kidney injury (AKI) [1, 2]. Production of reactive oxygen species is increased after IR injury and it has been demonstrated that oxidative stress induced inflammatory cells infiltration into the renal interstitium and release of proinflammatory cytokines [4,5,6]. These pathologic processes lead to apoptotic cell death and inflammatory cascades exacerbate oxidative stress around the inflamed lesion [7,8,9]. Inhibition of oxidative stress, renal inflammation, and apoptosis is an important approach to ameliorate ischemic kidney injury. EP4 signaling activates the phosphatidylinositol 3-kinase (PI3K) pathway leading to Akt activation [14, 15] and modulates the immune response in myocardial and cerebral
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
