Role of prostaglandin E2 receptor 4 in the modulation of apoptosis and mitophagy during ischemia/reperfusion injury in the kidney

Ding,Chenguang; Han,Feng; Xiang,Heli; Wang,Yuxiang; Dou,Meng; Xia,Xinxin; Li,Yang; Zheng,Jin; Ding,Xiaoming; Xue,Wujun; Tian,Puxun

doi:10.3892/mmr.2019.10576

Role of prostaglandin E2 receptor 4 in the modulation of apoptosis and mitophagy during ischemia/reperfusion injury in the kidney

Authors:
- Chenguang Ding
- Feng Han
- Heli Xiang
- Yuxiang Wang
- Meng Dou
- Xinxin Xia
- Yang Li
- Jin Zheng
- Xiaoming Ding
- Wujun Xue
- Puxun Tian
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Affiliations: Department of Kidney Transplantation, Nephropathy Hospital, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Traditional Chinese Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: August 8, 2019 https://doi.org/10.3892/mmr.2019.10576
Pages: 3337-3346

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Abstract

The mechanisms by which prostaglandin E2 receptor 4 (EP4) protects against renal ischemia‑reperfusion (I/R) injury (IRI) remain to be fully elucidated. In the present study, the protective effects of EP4 signaling on renal mitochondria and against renal IRI, as well as the underlying mechanisms, were investigated. A rat model of renal IRI was established. The right kidney was separated without damaging the artery clip, and the renal blood perfusion was then restored after 60 min. One group of animals was treated with EP4 agonists prior to I/R. The mitochondrial mass, the copy number of mitochondrial (mt)DNA, adenosine triphosphate (ATP) production and mitochondrial autophagy were analyzed. It was identified that renal IRI reduced the mitochondrial mass, decreased the mtDNA copy number and inhibited ATP production. The loss of renal mitochondria was attributed to the excessive mitochondrial autophagy induced by renal IRI. Pre‑treatment with EP4 agonist inhibited excessive mitochondrial autophagy, the loss of mitochondria and maintained and the energy imbalance within the cells. It was indicated that renal IRI causes excessive mitochondrial autophagy, which is one of the important causes of renal dysfunction.

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1	Nezu M, Souma T, Yu L, Suzuki T, Saigusa D, Ito S, Suzuki N and Yamamoto M: Transcription factor Nrf2 hyperactivation in early-phase renal ischemia-reperfusion injury prevents tubular damage progression. Kidney Int. 91:387–401. 2017. View Article : Google Scholar : PubMed/NCBI
2	Malek M and Nematbakhsh M: Renal ischemia/reperfusion injury; from pathophysiology to treatment. J Renal Inj Prev. 4:20–27. 2015.PubMed/NCBI
3	Zhu J, Chen X, Wang H and Yan Q: Catalpol protects mice against renal ischemia/reperfusion injury via suppressing PI3K/Akt-eNOS signaling and inflammation. Int J Clin Exp Med. 8:2038–2044. 2015.PubMed/NCBI
4	Kim N, Woo DC, Joo SJ, Song Y, Lee JJ, Woo CW, Kim ST, Hong S, Cho YM and Han DJ: Reduction in renal ischemia-reperfusion injury in mice by a phosphoinositide 3-kinase p110gamma-specific inhibitor. Transplantation. 99:2070–2076. 2015. View Article : Google Scholar : PubMed/NCBI
5	Meng QH, Liu HB and Wang JB: Polydatin ameliorates renal ischemia/reperfusion injury by decreasing apoptosis and oxidative stress through activating sonic hedgehog signaling pathway. Food Chem Toxicol. 96:215–225. 2016. View Article : Google Scholar : PubMed/NCBI
6	Ozbilgin S, Ozkardesler S, Akan M, Boztas N, Ozbilgin M, Ergur BU, Derici S, Guneli ME and Meseri R: Renal ischemia/reperfusion injury in diabetic rats: The role of local ischemic preconditioning. Biomed Res Int. 2016:85804752016. View Article : Google Scholar : PubMed/NCBI
7	Akan M, Ozbilgin S, Boztas N, Celik A, Ozkardesler S, Ergur BU, Guneli E, Sisman AR, Akokay P and Meseri R: Effect of magnesium sulfate on renal ischemia-reperfusion injury in streptozotocin-induced diabetic rats. Eur Rev Med Pharmacol Sci. 20:1642–1655. 2016.PubMed/NCBI
8	Wu SH, Chen XQ, Lü J and Wang MJ: BML-111 Attenuates renal ischemia/reperfusion injury via peroxisome proliferator-activated receptor-α-regulated heme oxygenase-1. Inflammation. 39:611–624. 2016. View Article : Google Scholar : PubMed/NCBI
9	Liu D, Jin F, Shu G, Xu X, Qi J, Kang X, Yu H, Lu K, Jiang S, Han F, et al: Enhanced efficiency of mitochondria-targeted peptide SS-31 for acute kidney injury by pH-responsive and AKI-kidney targeted nanopolyplexes. Biomaterials. 211:57–67. 2019. View Article : Google Scholar : PubMed/NCBI
10	Hu JB, Li SJ, Kang XQ, Qi J, Wu JH, Wang XJ, Xu XL, Ying XY, Jiang SP, You J and Du YZ: CD44-targeted hyaluronic acid-curcumin prodrug protects renal tubular epithelial cell survival from oxidative stress damage. Carbohydr Polym. 193:268–280. 2018. View Article : Google Scholar : PubMed/NCBI
11	Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I, Namba T, Kitamura H, Niimura F, Matsusaka T, Soga T, et al: Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol. 22:902–913. 2011. View Article : Google Scholar : PubMed/NCBI
12	Hamzawy M, Gouda SAA, Rashed L, Morcos MA, Shoukry H and Sharawy N: 22-oxacalcitriol prevents acute kidney injury via inhibition of apoptosis and enhancement of autophagy. Clin Exp Nephrol. 23:43–55. 2019. View Article : Google Scholar : PubMed/NCBI
13	Pang L: Inhibition of COX-2/PGE2/EP4 signaling protects against post-hypoxic apoptosis in H9C2 cardiomyocytes. Faseb J. 30:2016.
14	Xiao CY, Yuhki K, Hara A, Fujino T, Kuriyama S, Yamada T, Takayama K, Takahata O, Karibe H, Taniguchi T, et al: Prostaglandin E2 protects the heart from ischemia-reperfusion injury via its receptor subtype EP4. Circulation. 109:2462–2468. 2004. View Article : Google Scholar : PubMed/NCBI
15	Liang X, Lin L, Woodling NS, Wang Q, Anacker C, Pan T, Merchant M and Andreasson K: Signaling via the prostaglandin E₂ receptor EP4 exerts neuronal and vascular protection in a mouse model of cerebral ischemia. J Clin Invest. 121:4362–4371. 2011. View Article : Google Scholar : PubMed/NCBI
16	Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MS, Rakic P and Flavell RA: Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell. 94:325–337. 1998. View Article : Google Scholar : PubMed/NCBI
17	Wiktorowska-Owczarek A and Owczarek J: The effect of hypoxia on PGE2-stimulated cAMP generation in HMEC-1. Cell Mol Biol Lett. 20:213–221. 2015. View Article : Google Scholar : PubMed/NCBI
18	Li Y, Zhong D, Lei L, Jia Y, Zhou H and Yang B: Propofol prevents renal ischemia-reperfusion injury via inhibiting the oxidative stress pathways. Cell Physiol Biochem. 37:14–26. 2015. View Article : Google Scholar : PubMed/NCBI
19	Zhou S, Sun Y, Zhuang Y, Zhao W and Chen Y, Jiang B, Guo C, Zhang Z, Peng H and Chen Y: Effects of kallistatin on oxidative stress and inflammation on renal ischemia-reperfusion injury in mice. Curr Vasc Pharmacol. 13:265–273. 2015. View Article : Google Scholar : PubMed/NCBI
20	Cursio R, Colosetti P and Gugenheim J: Autophagy and liver ischemia-reperfusion injury. Biomed Res Int. 2015:4175902015. View Article : Google Scholar : PubMed/NCBI
21	Decuypere JP, Ceulemans LJ, Agostinis P, Monbaliu D, Naesens M, Pirenne J and Jochmans I: Autophagy and the kidney: Implications for ischemia-reperfusion injury and therapy. Am J Kidney Dis. 66:699–709. 2015. View Article : Google Scholar : PubMed/NCBI
22	Li H, Liu X, Zhu Y, Liu Y and Wang Y: Magnolol derivative 002C-3 protects brain against ischemia-reperfusion injury via inhibiting apoptosis and autophagy. Neurosci Lett. 588:178–183. 2015. View Article : Google Scholar : PubMed/NCBI
23	Qiao PF, Yao L, Zhang XC, Li GD and Wu DQ: Heat shock pretreatment improves stem cell repair following ischemia- reperfusion injury via autophagy. World J Gastroenterol. 21:12822–12834. 2015. View Article : Google Scholar : PubMed/NCBI
24	Jiang M, Liu K, Luo J and Dong Z: Autophagy is a renoprotective mechanism during in vitro hypoxia and in vivo ischemia-reperfusion injury. Am J Pathol. 176:1181–1192. 2010. View Article : Google Scholar : PubMed/NCBI
25	Tan KY, Li CY, Li YF, Fei J, Yang B, Fu YJ and Li F: Real-time monitoring ATP in mitochondrion of living cells: A specific fluorescent probe for ATP by dual recognition sites. Anal Chem. 89:1749–1756. 2017. View Article : Google Scholar : PubMed/NCBI
26	Lewis SC, Uchiyama LF and Nunnari J: ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science. 353:aaf55492016. View Article : Google Scholar : PubMed/NCBI
27	Lauritzen KH, Kleppa L, Aronsen JM, Eide L, Carlsen H, Haugen ØP, Sjaastad I, Klungland A, Rasmussen LJ, Attramadal H, et al: Impaired dynamics and function of mitochondria caused by mtDNA toxicity leads to heart failure. Am J Physiol Heart Circ Physiol. 309:H434–H449. 2015. View Article : Google Scholar : PubMed/NCBI
28	Cheng N, Lo YS, Ansari MI, Ho KC, Jeng ST, Lin NS and Dai H: Correlation between mtDNA complexity and mtDNA replication mode in developing cotyledon mitochondria during mung bean seed germination. New Phytol. 213:751–763. 2017. View Article : Google Scholar : PubMed/NCBI
29	Hämäläinen RH: Mitochondria and mtDNA integrity in stem cell function and differentiation. Curr Opin Genet Dev. 38:83–89. 2016. View Article : Google Scholar : PubMed/NCBI
30	Baruffini E, Ferrari J, Dallabona C, Donnini C and Lodi T: Polymorphisms in DNA polymerase γ affect the mtDNA stability and the NRTI-induced mitochondrial toxicity in Saccharomyces cerevisiae. Mitochondrion. 20:52–63. 2015. View Article : Google Scholar : PubMed/NCBI
31	Sokolowska M, Chen LY, Liu Y, Martinez-Anton A, Qi HY, Logun C, Alsaaty S, Park YH, Kastner DL, Chae JJ and Shelhamer JH: Prostaglandin E2 inhibits NLRP3 inflammasome activation through EP4 receptor and intracellular cAMP in human macrophages. J Immunol. 194:5472–5487. 2015. View Article : Google Scholar : PubMed/NCBI
32	Chang HH, Young SH, Sinnett-Smith J, Chou CE, Moro A, Hertzer KM, Hines OJ, Rozengurt E and Eibl G: Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA- and EP1/Ca2+-mediated mechanism in the human pancreatic carcinoma cell line PANC-1. Am J Physiol Cell Physiol. 309:C639–C649. 2015. View Article : Google Scholar : PubMed/NCBI
33	Chang HH, Young S, Sinnett-Smith J, Chou CEN, Hines OJ, Rozengurt E and Eibl G: Abstract 1028: Prostaglandin E2 activates the mTORC1 pathway through an EP4/cAMP/PKA and EP1/calcium-mediated mechanisms in human pancreatic carcinoma cells. Am J Physiol Cell Physiol. 309:2015.
34	Xu S, Ge JP, Zhang ZY and Zhou WQ: AB063. A prostaglandin E (PGE) receptor EP4 is involved in the cell growth and invasion of prostate cancer via the cAMP-PKA/PI3K-AKT signaling pathway. Transl Androl Urol. 6 (Suppl 3):2017. View Article : Google Scholar : PubMed/NCBI