Paricalcitol attenuates lipopolysaccharide-induced inflammation and apoptosis in proximal tubular cells through the prostaglandin E₂ receptor EP4.
10.23876/j.krcp.2017.36.2.145
- Author:
Yu Ah HONG
1
;
Keum Jin YANG
;
So Young JUNG
;
Yoon Kyung CHANG
;
Cheol Whee PARK
;
Chul Woo YANG
;
Suk Young KIM
;
Hyeon Seok HWANG
Author Information
1. Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea. hwanghs@catholic.ac.kr
- Publication Type:Original Article
- Keywords:
Apoptosis;
Ergocalciferols;
Inflammation;
Lipopolysaccharide;
Prostaglandin EP4 receptor
- MeSH:
Apoptosis*;
Cell Death;
Cyclooxygenase 2;
Cytokines;
Ergocalciferols;
Humans;
Inflammation*;
Phosphorylation;
Receptors, Prostaglandin E, EP4 Subtype;
RNA, Small Interfering;
Vitamin D
- From:Kidney Research and Clinical Practice
2017;36(2):145-158
- CountryRepublic of Korea
- Language:English
-
Abstract:
BACKGROUND: Vitamin D is considered to exert a protective effect on various renal diseases but its underlying molecular mechanism remains poorly understood. This study aimed to determine whether paricalcitol attenuates inflammation and apoptosis during lipopolysaccharide (LPS)-induced renal proximal tubular cell injury through the prostaglandin E₂ (PGE₂) receptor EP4. METHODS: Human renal tubular epithelial (HK-2) cells were pretreated with paricalcitol (2 ng/mL) for 1 hour and exposed to LPS (1 μg/mL). The effects of paricalcitol pretreatment in relation to an EP4 blockade using AH-23848 or EP4 small interfering RNA (siRNA) were investigated. RESULTS: The expression of cyclooxygenase-2, PGE₂, and EP4 were significantly increased in LPS-exposed HK-2 cells treated with paricalcitol compared with cells exposed to LPS only. Paricalcitol prevented cell death induced by LPS exposure, and the cotreatment of AH-23848 or EP4 siRNA offset these cell-protective effects. The phosphorylation and nuclear translocation of p65 nuclear factor-kappaB (NF-κB) were decreased and the phosphorylation of Akt was increased in LPS-exposed cells with paricalcitol treatment. AH-23848 or EP4 siRNA inhibited the suppressive effects of paricalcitol on p65 NF-κB nuclear translocation and the activation of Akt. The production of proinflammatory cytokines and the number of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were attenuated by paricalcitol in LPS exposed HK-2 cells. The cotreatment with an EP4 antagonist abolished these anti-inflammatory and antiapoptotic effects. CONCLUSION: EP4 plays a pivotal role in anti-inflammatory and antiapoptotic effects through Akt and NF-κB signaling after paricalcitol pretreatment in LPS-induced renal proximal tubule cell injury.
