The role of eicosanoids in renal diseases – potential therapeutic possibilities

  • Maciej Fijałkowski Pomeranian Medical University, Department of Nephrology, Transplantology and Internal Medicine
  • Joanna Stępniewska Pomeranian Medical University, Department of Nephrology, Transplantology and Internal Medicine
  • Maciej Domański Pomeranian Medical University, Department of Nephrology, Transplantology and Internal Medicine
  • Kazimierz Ciechanowski Pomeranian Medical University, Department of Nephrology, Transplantology and Internal Medicine
  • Edyta Golembiewska Pomeranian Medical University, Department of Nephrology, Transplantology and Internal Medicine


Eicosanoids are biologically active molecules that are created in the process of oxidation of arachidonic acid (AA) which is a constituent of the cell membrane phospholipids. Throughout the years it was evidenced by experiments that the lipid and lipid-derived metabolites play an important role in physiological and pathological processes in the kidneys. They are being considered as biomarkers in detecting acute kidney injury, nephrotoxicity, glomerulonephritis and early stages of diabetic nephropathy because of their participation in inflammatory processes and in oxidative stress. They might be also considered as potential novel targets of therapy. However, the role of eicosanoids is still not fully clear and needs to be explored in future studies. In this brief review, studies on the role of eicosanoids in physiological and pathological conditions, e.g. acute kidney injury (AKI) and chronic kidney disease (CKD), and in different renal replacement therapies, including kidney transplantation, are being discussed.



Averna M, Barbagallo CM, Ganci A, Giammarresi C, Cefalù A B, Sparacino V, Davì G (2001). Determinants of enhanced thromboxane biosynthesis in renal transplantation. Kidney Int 59(4): 1574-1579. doi:10.1046/j.1523-1755.2001.0590041574.x

Badr K F, Kelley V E, Rennke H G, & Brenner B M (1986). Roles for thromboxane A2 and leukotrienes in endotoxin-induced acute renal failure. Kidney Int 30(4): 474-480.

Burdan F, Chałas A & Szumiło J (2006). [Cyclooxygenase and prostanoids--biological implications]. Postepy Hig Med Dosw (Online) 60: 129-141.

Chaudhari A & Kirschenbaum M A (1983). Mechanism of increased renal prostaglandin E2 in uranyl nitrate-induced acute renal failure. Prostaglandins 26(5):689-699.

Chen H, Cao G, Chen D Q, Wang M, Vaziri N D, Zhang Z H, Zhao Y Y (2016). Metabolomics insights into activated redox signaling and lipid metabolism dysfunction in chronic kidney disease progression. Redox Biol 10: 168-178. doi:10.1016/j.redox.2016.09.014

Courivaud C, Bamoulid J, Loupy A, Deschamps M, Ferrand C, Le Corre D, Ducloux D (2009). Influence of cyclooxygenase-2 (COX-2) gene promoter polymorphism -765 on graft loss after renal transplantation. Am J Transplant 9(12): 2752-2757. doi:10.1111/j.1600-6143.2009.02830.x

Câmara N O, Martins J O, Landgraf R G & Jancar S (2009). Emerging roles for eicosanoids in renal diseases. Curr Opin Nephrol Hypertens 18(1): 21-27. doi:10.1097/MNH.0b013e32831a9df7

Dennis E A & Norris P C (2015). Eicosanoid storm in infection and inflammation. Nat Rev Immunol 15(8): 511-523. doi:10.1038/nri3859

Dreisbach A W, Smith S V, Kyle P B, Ramaiah M, Amenuke M, Garrett M R, Roman R J (2014). Urinary CYP eicosanoid excretion correlates with glomerular filtration in African-Americans with chronic kidney disease. Prostaglandins Other Lipid Mediat 113-115: 45-51. doi:10.1016/j.prostaglandins.2014.08.002

el-Sharabasy M M & el-Naggar M N (1991). Prostaglandin E2 in renal transplant recipients. Acta Med Hung 48(3-4): 225-229.

Ferreri N R, Hao S, Pedraza P L, Escalante B & Vio C P (2012). Eicosanoids and tumor necrosis factor-alpha in the kidney. Prostaglandins Other Lipid Mediat 98(3-4): 101-106. doi:10.1016/j.prostaglandins.2011.11.002

Gainza F J, Quintanilla N, Pijoan J I, Delgado S, Urbizu J M & Lampreabe I (2006). Role of prostacyclin (epoprostenol) as anticoagulant in continuous renal replacement therapies: efficacy, security and cost analysis. J Nephrol 19(5): 648-655.

Hao C M & Breyer M D (2007). Physiologic and pathophysiologic roles of lipid mediators in the kidney. Kidney Int 71(11): 1105-1115. doi:10.1038/

Helal I, Fick-Brosnahan G M, Reed-Gitomer B & Schrier R W (2012). Glomerular hyperfiltration: definitions, mechanisms and clinical implications. Nat Rev Nephrol 8(5): 293-300. doi:10.1038/nrneph.2012.19

Hoozemans J J, Rozemuller J M, van Haastert E S, Veerhuis R & Eikelenboom P (2008). Cyclooxygenase-1 and -2 in the different stages of Alzheimer's disease pathology. Curr Pharm Des 14(14): 1419-1427.

Imanishi M, Ikegami M, Nishioka T, Ishii T, Uemura T, Kunikata S, Kurita T (1990). [The effects of thromboxane A2 synthetase inhibitor on chronic rejection of kidney transplantation]. Nihon Hinyokika Gakkai Zasshi 81(6): 895-901.

Imig J D (2013). Epoxyeicosatrienoic acids, 20-hydroxyeicosatetraenoic acid, and renal microvascular function. Prostaglandins Other Lipid Mediat 104-105: 2-7. doi:10.1016/j.prostaglandins.2013.01.002

Imig J D (2015). Epoxyeicosatrienoic acids, hypertension, and kidney injury. Hypertension 65(3): 476-482. doi:10.1161/HYPERTENSIONAHA.114.03585

Jia Z, Wang H & Yang T (2012). Microsomal prostaglandin E synthase 1 deletion retards renal disease progression but exacerbates anemia in mice with renal mass reduction. Hypertension 59(1): 122-128. doi:10.1161/HYPERTENSIONAHA.111.178897

Kang S H, Oyama T T, Kennefick T M, Thompson M M & Anderson S (2000). Impaired adaptation to renal mass reduction in the polycystic rat. Am J Kidney Dis 35(5): 923-929.

Klawitter J, McFann K, Pennington A T, Abebe K Z, Brosnahan G, Cadnapaphornchai M A, Schrier R W (2014). Bioactive lipid mediators in polycystic kidney disease. J Lipid Res 55(6): 1139-1149. doi:10.1194/jlr.P042176

Koyama A, Fujita T, Gejyo F, Origasa H, Isono M, Kurumatani H, Yamada S (2015). Orally active prostacyclin analogue beraprost sodium in patients with chronic kidney disease: a randomized, double-blind, placebo-controlled, phase II dose finding trial. BMC Nephrol 16: 165. doi:10.1186/s12882-015-0130-5

Kramer H J, Mohaupt M G, Pinoli F, Bäcker A, Meyer-Lehnert H & Schlebusch H (1993). Effects of thromboxane A2 receptor blockade on oliguric ischemic acute renal failure in conscious rats. J Am Soc Nephrol 4(1): 50-57.

Makino H, Tanaka I, Mukoyama M, Sugawara A, Mori K, Muro S, Nakao K (2002). Prevention of diabetic nephropathy in rats by prostaglandin E receptor EP1-selective antagonist. J Am Soc Nephrol 13(7): 1757-1765.

Mangino M J, Anderson C B, Deschryver K & Turk J (1987). Arachidonate lipoxygenase products and renal allograft rejection in dogs. Transplantation 44(6):805-808.

Mederle K, Meurer M, Castrop H & Höcherl K (2015). Inhibition of COX-1 attenuates the formation of thromboxane A2 and ameliorates the acute decrease in glomerular filtration rate in endotoxemic mice. Am J Physiol Renal Physiol 309(4): F332-340. doi:10.1152/ajprenal.00567.2014

Nasrallah R, Hassouneh R & Hébert R L (2014). Chronic kidney disease: targeting prostaglandin E2 receptors. Am J Physiol Renal Physiol 307(3): F243-250. doi:10.1152/ajprenal.00224.2014

Nasrallah R, Hassouneh R & Hébert R L (2016). PGE2, Kidney Disease, and Cardiovascular Risk: Beyond Hypertension and Diabetes. J Am Soc Nephrol 27(3): 666-676. doi:10.1681/ASN.2015050528

Nasrallah R, Hassouneh R, Zimpelmann J, Karam A J, Thibodeau J F, Burger D, Hébert R L (2015). Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors. Lab Invest 95(9): 1044-1055. doi:10.1038/labinvest.2015.79

Nasrallah R, Laneuville O, Ferguson S & Hébert R L (2001). Effect of COX-2 inhibitor NS-398 on expression of PGE2 receptor subtypes in M-1 mouse CCD cells. Am J Physiol Renal Physiol 281(1): F123-132. doi:10.1152/ajprenal.2001.281.1.F123

Nasrallah R, Xiong H & Hébert R L (2007). Renal prostaglandin E2 receptor (EP) expression profile is altered in streptozotocin and B6-Ins2Akita type I diabetic mice. Am J Physiol Renal Physiol 292(1): F278-284. doi:10.1152/ajprenal.00089.2006

Nørregaard R, Kwon T H & Frøkiær J (2015). Physiology and pathophysiology of cyclooxygenase-2 and prostaglandin E2 in the kidney. Kidney Res Clin Pract 34(4):194-200. doi:10.1016/j.krcp.2015.10.004

Park F, Sweeney W E, Jia G, Akbulut T, Mueller B, Falck J R, Avner E D (2009). Chronic blockade of 20-HETE synthesis reduces polycystic kidney disease in an orthologous rat model of ARPKD. Am J Physiol Renal Physiol 296(3): F575-582. doi:10.1152/ajprenal.90705.2008

Regner K R (2012). Dual role of microsomal prostaglandin E synthase 1 in chronic kidney disease. Hypertension 59(1): 12-13. doi:10.1161/HYPERTENSIONAHA.111.180034

Regner K R, Zuk A, Van Why S K, Shames B D, Ryan R P, Falck J R, Roman R J (2009). Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury. Kidney Int 75(5): 511-517. doi:10.1038/ki.2008.600

Reinhold S W, Vitzthum H, Filbeck T, Wolf K, Lattas C, Riegger G A, Krämer B K (2006). Gene expression of 5-, 12-, and 15-lipoxygenases and leukotriene receptors along the rat nephron. Am J Physiol Renal Physiol 290(4): F864-872. doi:10.1152/ajprenal.00169.2005

Ren Y, D'Ambrosio M A, Garvin J L, Wang H & Carretero O A (2013). Prostaglandin E2 mediates connecting tubule glomerular feedback. Hypertension 62(6): 1123-1128. doi:10.1161/HYPERTENSIONAHA.113.02040

Roman R J, Akbulut T, Park F & Regner K R (2011). 20-HETE in acute kidney injury. Kidney Int 79(1): 10-13. doi:10.1038/ki.2010.396

Sales K J & Jabbour H N (2003). Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction 126(5): 559-567.

Sales K J, Katz A A, Howard B, Soeters R P, Millar R P & Jabbour H N (2002). Cyclooxygenase-1 is up-regulated in cervical carcinomas: autocrine/paracrine regulation of cyclooxygenase-2, prostaglandin e receptors, and angiogenic factors by cyclooxygenase-1. Cancer Res 62(2): 424-432.

Sałata D & Dołęgowska B (2014). [Bioactive lipids in kidney physiology and pathophysiology]. Postepy Hig Med Dosw (Online) 68: 73-83. doi:10.5604/17322693.1086412

Smith S R, Creech E A, Schaffer A V, Martin L L, Rakhit A, Douglas F L, Coffman T M (1992). Effects of thromboxane synthase inhibition with CGS 13080 in human cyclosporine nephrotoxicity. Kidney Int 41(1): 199-205.

Smith W S & Murphy R C (2002). The Eicosanoids: Cyclooxygenase, Lipoxygenase and Epoxygenase Pathways. In D. E. Vance & J. E. Vance (Eds.), Biochemistry of lipids, lipoproteins, and membranes (4th ed. ed., Vol. 36, pp. 341-371). Amsterdam London: Elsevier.

Spargias K, Adreanides E, Demerouti E, Gkouziouta A, Manginas A, Pavlides G, Cokkinos D V (2009). Iloprost prevents contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography or intervention. Circulation 120(18): 1793-1799. doi:10.1161/CIRCULATIONAHA.109.863159

Sporková A, Kopkan L, Varcabová S, Husková Z, Hwang S H, Hammock B D, Cervenka L (2011). Role of cytochrome P-450 metabolites in the regulation of renal function and blood pressure in 2-kidney 1-clip hypertensive rats. Am J Physiol Regul Integr Comp Physiol 300(6): R1468-1475. doi:10.1152/ajpregu.00215.2010

Spurney R F, Fan P Y, Ruiz P, Sanfilippo F, Pisetsky D S & Coffman T M (1992). Thromboxane receptor blockade reduces renal injury in murine lupus nephritis. Kidney Int 41(4): 973-982.

Srivastava T, Alon U S, Cudmore P A, Tarakji B, Kats A, Garola R E, Sharma M (2014). Cyclooxygenase-2, prostaglandin E2, and prostanoid receptor EP2 in fluid flow shear stress-mediated injury in the solitary kidney. Am J Physiol Renal Physiol 307(12): F1323-1333. doi:10.1152/ajprenal.00335.2014

Stępniewska J, Dołęgowska B, Puchałowicz K, Gołembiewska E & Ciechanowski K (2017). Bioactive lipids derived from arachidonic acid metabolism in different types of renal replacement therapy. Chem Phys Lipids 206: 71-77. doi:10.1016/j.chemphyslip.2017.05.003

Swartz R D, Flamenbaum W, Dubrow A, Hall J C, Crow J W & Cato A (1988). Epoprostenol (PGI2, prostacyclin) during high-risk hemodialysis: preventing further bleeding complications. J Clin Pharmacol 28(9): 818-825.

Uriu K, Kaizu K, Hashimoto O, Komine N & Etoh S (1994). Acute and chronic effects of thromboxane A2 inhibition on the renal hemodynamics in streptozotocin-induced diabetic rats. Kidney Int 45(3): 794-802.

Uyar M E, Yucel P, Ilin S, Bal Z, Yildirim S, Uyar A S, Sezer S (2016). Iloprost as an acute kidney injury-triggering agent in severely atherosclerotic patients. Cardiovasc J Afr 27(3): 128-133. doi:10.5830/CVJA-2015-051

Vio C P, Quiroz-Munoz M, Cuevas C A, Cespedes C & Ferreri N R (2012). Prostaglandin E2 EP3 receptor regulates cyclooxygenase-2 expression in the kidney. Am J Physiol Renal Physiol 303(3): F449-457. doi:10.1152/ajprenal.00634.2011

Vukicevic S, Simic P, Borovecki F, Grgurevic L, Rogic D, Orlic I, Paralkar V M (2006). Role of EP2 and EP4 receptor-selective agonists of prostaglandin E(2) in acute and chronic kidney failure. Kidney Int 70(6): 1099-1106. doi:10.1038/

Wang C, Luo Z, Kohan D, Wellstein A, Jose P A, Welch W J, Wang D (2015). Thromboxane prostanoid receptors enhance contractions, endothelin-1, and oxidative stress in microvessels from mice with chronic kidney disease. Hypertension 65(5): 1055-1063. doi:10.1161/HYPERTENSIONAHA.115.05244

Wang W, Zolty E, Falk S, Summer S, Stearman R, Geraci M & Schrier R (2007). Prostacyclin in endotoxemia-induced acute kidney injury: cyclooxygenase inhibition and renal prostacyclin synthase transgenic mice. Am J Physiol Renal Physiol 293(4): F1131-1136. doi:10.1152/ajprenal.00212.2007

Ye W, Zhang H, Hillas E, Kohan D E, Miller R L, Nelson R D, Yang T (2006). Expression and function of COX isoforms in renal medulla: evidence for regulation of salt sensitivity and blood pressure. Am J Physiol Renal Physio, 290(2): F542-549. doi:10.1152/ajprenal.00232.2005

Zhao Y Y (2013). Metabolomics in chronic kidney disease. Clin Chim Acta 422: 59-69. doi:10.1016/j.cca.2013.03.033

Zhao Y Y & Lint R C (2014). Metabolomics in nephrotoxicity. Adv Clin Chem 65: 69-89.

Zhao Y Y, Vaziri N D & Lin R C (2015). Lipidomics: new insight into kidney disease. Adv Clin Chem 68: 153-175. doi:10.1016/bs.acc.2014.11.002