Pretreatment with paricalcitol attenuates inflammation in ischemia–reperfusion injury via the up-regulation of cyclooxygenase-2 and prostaglandin E2

Abstract The effect of paricalcitolon renal ischemia-reperfusion injury (IRI) has not been investigated. We examined whether paricalcitolis effective in preventing inflammation in a mouse model of IRI, and evaluated the cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) pathways as a protective mechanismof paricalcitol. Paricalcitol(0.3 μg/kg) was administered to male C57BL/6 mice 24 h before IRI. Bilateral kidneys were subjected to 23 min of ischemia, and mice were killed 72 h after IRI. The effects of paricalcitolon renal IRI were evaluated in terms of renal function, tubular necrosis, apoptotic cell death, inflammatory cell infiltration and inflammatory cytokines. The effects of paricalcitolon COX-2, PGE2 and its receptors were investigated. Paricalcitolpretreatment improved renal function (decreased blood urea nitrogenand serum creatinine levels), tubular necrosisand apoptotic cell death in IRI-mice kidneys. The infiltration of inflammatory cells (T cells and macrophages), and the production of proinflammatory cytokines (RANTES, tumor necrosis factor-α, interleukin-1β and interferon-γ) were reduced in paricalcitol-treated mice with IRI. Paricalcitolup-regulated COX-2 expression, PGE2 synthesis and mRNA expression of receptor subtype EP4 in post-ischemic renal tissue. The cotreatment of a selective COX-2 inhibitorwith paricalcitolrestored functional injury and tubular necrosisin paricalcitol-treated mice with IRI. Our study demonstrates that paricalcitolpretreatment prevents renal IRI via the inhibition of renal inflammation, and the up-regulation of COX-2 and PGE2 is one of the protective mechanismsof paricalcitolin renal IRI.