Cyclooxygenase 2 inhibition slows disease progression and improves the altered renal lipid mediator profile in the Pkd2WS25/− mouse model of autosomal dominant polycystic kidney disease

  • Md Monirujjaman
  • Harold M. AukemaEmail author
Original Article



Increased levels of cyclooxygenase (COX) derived oxylipins is the earliest and most consistent alteration in the renal oxylipin profile in diverse models of cystic kidney diseases. Therefore, we examined whether a COX2 inhibitor would reduce disease progression in the Pkd2WS25/− mouse model of autosomal dominant polycystic kidney disease (ADPKD).


Weanling normal and diseased male Pkd2 mice were provided diets that provided 0 or 50 mg celecoxib/kg body weight/day, for 13 weeks. Renal disease and function were assessed by histomorphometric analysis of renal cysts and measurement of serum creatinine and urea nitrogen (SUN) levels. Targeted lipidomic analysis of renal oxylipins was performed by HPLC–MS/MS.


Diseased mice had significant cyst involvement and reduced renal function as indicated by elevated serum creatinine and SUN. Celecoxib reduced cyst area by 48%, cyst volume by 70%, and serum creatinine and SUN by 20% and 16%, respectively. Consistent with our previous studies, 8 of the 11 COX derived oxylipins were higher in diseased kidneys. In addition, 24 of 33 lipoxygenase (LOX) derived oxylipins and 7 of 16 cytochrome P450 (CYP) derived oxylipins were lower in diseased kidneys. Celecoxib reduced total and five of the eight individual elevated COX oxylipins and increased 5 of 24 LOX and 5 of 7 CYP oxylipins that were reduced by disease.


COX2 inhibition ameliorates disease progression, improves renal function and improves the altered oxylipins in Pkd2 mice. This represents a potential new approach for treatment of ADPKD, a disorder for which no effective treatment currently exists.


Autosomal dominant polycystic kidney disease (ADPKD) Celecoxib Cyclooxygenase (COX) Cyst Oxylipin 



We gratefully acknowledge T. Winter for her technical assistance.


This study was supported by a Grant from the Natural Sciences and Engineering Research Council of Canada (NSERC) (RGPIN-2015-03733) to HMA. Research studentship support was from the University of Manitoba Graduate Fellowship, Queen Elizabeth II Diamond Jubilee Scholarship, Janet Fabro McComb Scholarship and GETS Scholarship programs to MM.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no conflict of interest.

Ethical statement

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of University of Manitoba.

Supplementary material

40620_2018_578_MOESM1_ESM.docx (31 kb)
Supplementary material 1 (DOCX 30 KB)


  1. 1.
    Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337CrossRefGoogle Scholar
  2. 2.
    Blanchette CM, Liang C, Lubeck DP, Newsome B, Rossetti S, Gu X, Gutierrez B, Lin ND (2015) Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease. Drugs Context 4:212275Google Scholar
  3. 3.
    Luo F, Tao YH (2018) Nephronophthisis: a review of genotype–phenotype correlation. Nephrology (Carlton). Google Scholar
  4. 4.
    Magistroni R, Boletta (2017) Defective glycolysis and the use of 2-deoxy-d-glucose in polycystic kidney disease: from animal models to humans. J Nephrol 30:511–519CrossRefGoogle Scholar
  5. 5.
    Stewart JH (1994) End-stage renal failure appears earlier in men than in women with polycystic kidney disease. Am J Kidney Dis 24:181–183CrossRefGoogle Scholar
  6. 6.
    Yamaguchi T, Devassy JG, Gabbs M, Ravandi A, Nagao S, Aukema HM (2015) Dietary flax oil rich in alpha-linolenic acid reduces renal disease and oxylipin abnormalities, including formation of docosahexaenoic acid derived oxylipins in the CD1-pcy/pcy mouse model of nephronophthisis. Prostaglandins Leukot Essent Fatty Acids 94:83–89CrossRefGoogle Scholar
  7. 7.
    Yamaguchi T, Lysecki C, Reid A, Nagao S, Aukema HM (2014) Renal cyclooxygenase products are higher and lipoxygenase products are lower in early disease in the pcy mouse model of adolescent nephronophthisis. Lipids 49:39–47CrossRefGoogle Scholar
  8. 8.
    Ibrahim NH, Jia Y, Devassy JG, Yamaguchi T, Aukema HM (2014) Renal cyclooxygenase and lipoxygenase products are altered in polycystic kidneys and by dietary soy protein and fish oil treatment in the Han:SPRD-Cy rat. Mol Nutr Food Res 58:768–781CrossRefGoogle Scholar
  9. 9.
    Monirujjaman M, Devassy JG, Yamaguchi T, Sidhu N, Kugita M, Gabbs M, Nagao S, Zhou J, Ravandi A, Aukema HM (2017) Distinct oxylipin alterations in diverse models of cystic kidney diseases. Biochim Biophys Acta 1862:1562–1574CrossRefGoogle Scholar
  10. 10.
    Gabbs M, Leng S, Devassy JG, Monirujjaman M, Aukema HM (2015) Advances in our understanding of oxylipins derived from dietary PUFAs. Adv Nutr 6:513–540CrossRefGoogle Scholar
  11. 11.
    Camara NO, Martins JO, Landgraf RG, Jancar S (2009) Emerging roles for eicosanoids in renal diseases. Curr Opin Nephrol Hypertens 18:21–27CrossRefGoogle Scholar
  12. 12.
    Warford-Woolgar L, Peng CY, Shuhyta J, Wakefield A, Sankaran D, Ogborn M, Aukema HM (2006) Selectivity of cyclooxygenase isoform activity and prostanoid production in normal and diseased Han:SPRD-cy rat kidneys. Am J Physiol Renal Physiol 290:F897–F904CrossRefGoogle Scholar
  13. 13.
    Aukema HM, Adolphe J, Mishra S, Jiang J, Cuozzo FP, Ogborn MR (2003) Alterations in renal cytosolic phospholipase A2 and cyclooxygenases in polycystic kidney disease. FASEB J 17:298–300CrossRefGoogle Scholar
  14. 14.
    Bos CL, Richel DJ, Ritsema T, Peppelenbosch MP, Versteeg HH (2004) Prostanoids and prostanoid receptors in signal transduction. Int J Biochem Cell Biol 36:1187–1205CrossRefGoogle Scholar
  15. 15.
    Diaz-Munoz MD, Osma-Garcia IC, Fresno M, Iñiguez MA (2012) Involvement of PGE2 and the cAMP signalling pathway in the up-regulation of COX-2 and mPGES-1 expression in LPS-activated macrophages. Biochem J 443:451–461CrossRefGoogle Scholar
  16. 16.
    Klein T, Shephard P, Kleinert H, Kömhoff M (2007) Regulation of cyclooxygenase-2 expression by cyclic AMP. Biochim Biophys Acta 1773:1605–1618CrossRefGoogle Scholar
  17. 17.
    Yamaguchi T, Nagao S, Kasahara M, Kömhoff M (1997) Renal accumulation and excretion of cyclic adenosine monophosphate in a murine model of slowly progressive polycystic kidney disease. Am J Kidney Dis 30:703–709CrossRefGoogle Scholar
  18. 18.
    Putnam WC, Swenson SM, Reif GA, Wallace DP, Helmkamp GM Jr, Grantham JJ (2007) Identification of a forskolin-like molecule in human renal cysts. J Am Soc Nephrol 18:934–943CrossRefGoogle Scholar
  19. 19.
    Yamaguchi T, Pelling JC, Ramaswamy NT, et Eppler JW, Wallace DP, Nagao S, Rome LA, Sullivan LP, Grantham JJ (2000) cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int 57:1460–1471CrossRefGoogle Scholar
  20. 20.
    Elberg G, Elberg D, Lewis TV, Guruswamy S, Chen L, Logan CJ, Chan MD, Turman MA (2007) EP2 receptor mediates PGE2-induced cystogenesis of human renal epithelial cells. Am J Physiol Renal Physiol 293:F1622–F1632CrossRefGoogle Scholar
  21. 21.
    Elberg D, Turman MA, Pullen N, Elberg G (2012) Prostaglandin E2 stimulates cystogenesis through EP4 receptor in IMCD-3 cells. Prostaglandins Other Lipid Mediat 98:11–16CrossRefGoogle Scholar
  22. 22.
    Yang B, Sonawane ND, Zhao D, Somlo S, Verkman AS (2008) Small-molecule CFTR inhibitors slow cyst growth in polycystic kidney disease. J Am Soc Nephrol 19:1300–1310CrossRefGoogle Scholar
  23. 23.
    Albaqumi M, Srivastava S, Li Z, Zhdnova O, Wulff H, Itani O, Wallace DP, Skolnik EY (2008) KCa3.1 potassium channels are critical for cAMP-dependent chloride secretion and cyst growth in autosomal-dominant polycystic kidney disease. Kidney Int 74:740–749CrossRefGoogle Scholar
  24. 24.
    Ibrahim NH, Gregoire M, Devassy JG, Wu Y, Yoshihara D, Yamaguchi T, Nagao S, Aukema HM (2015) Cyclooxygenase product inhibition with acetylsalicylic acid slows disease progression in the Han:SPRD-Cy rat model of polycystic kidney disease. Prostaglandins Other Lipid Mediat 116–117:19–25CrossRefGoogle Scholar
  25. 25.
    Xu T, Wang NS, Fu LL, Ye CY, Yu SQ, Mei CL (2012) Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway. Mol Biol Rep 39:7743–7753CrossRefGoogle Scholar
  26. 26.
    Sankaran D, Bankovic-Calic N, Ogborn MR, Crow G, Aukema HM (2007) Selective COX-2 inhibition markedly slows disease progression and attenuates altered prostanoid production in Han:SPRD-cy rats with inherited kidney disease. Am J Physiol Renal Physiol 293:F821–F830CrossRefGoogle Scholar
  27. 27.
    Horl WH (2010) Nonsteroidal anti-inflammatory drugs and the kidney. Pharmaceuticals (Basel) 3:2291–2321CrossRefGoogle Scholar
  28. 28.
    Wu G, D’Agati V, Cai Y, Markowitz G, Park JH, Reynolds DM, Maeda Y, Le TC, Hou H Jr, Kucherlapati R, Edelmann W, Somlo S (1998) Somatic inactivation of Pkd2 results in polycystic kidney disease. Cell 93:177–188CrossRefGoogle Scholar
  29. 29.
    Olson JM, Haas AW, Lor J, McKee HS, Cook ME (2017) A Comparison of the anti-inflammatory effects of Cis-9, Trans-11 Conjugated linoleic acid to celecoxib in the collagen-induced arthritis model. Lipids 52:151–159CrossRefGoogle Scholar
  30. 30.
    Nasrallah R, Robertson SJ, Karsh J, Hébert RL (2013) Celecoxib modifies glomerular basement membrane, mesangium and podocytes in OVE26 mice, but ibuprofen is more detrimental. Clin Sci (Lond) 124:685–694CrossRefGoogle Scholar
  31. 31.
    Yamaguchi T, Devassy JG, Monirujjaman M, Gabbs M, Aukema HM (2016) Lack of benefit of early intervention with dietary flax and fish oil and soy protein in orthologous rodent models of human hereditary polycystic kidney disease. PLoS One 11:e0155790CrossRefGoogle Scholar
  32. 32.
    Sankaran D, Lu J, Bankovic-Calic N, Ogborn MR, Aukema HM (2004) Modulation of renal injury in pcy mice by dietary fat containing n-3 fatty acids depends on the level and type of fat. Lipids 39:207–214CrossRefGoogle Scholar
  33. 33.
    Hall LM, Murphy RC (1998) Electrospray mass spectrometric analysis of 5-hydroperoxy and 5-hydroxyeicosatetraenoic acids generated by lipid peroxidation of red blood cell ghost phospholipids. J Am Soc Mass Spectrom 9:527–532CrossRefGoogle Scholar
  34. 34.
    Messchendorp AL, van Londen M, Taylor JM, de Borst MH, Navis G, Casteleijn NF et al (2018) Kidney function reserve capacity in early and later stage autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. Google Scholar
  35. 35.
    Ghata J, Cowley BD Jr (2017) Polycystic kidney disease. Compr Physiol 7:945–975CrossRefGoogle Scholar
  36. 36.
    Yamaguchi T, Nagao S, Wallace DP, Belibi FA, Cowley BD, Pelling JC, Grantham JJ (2003) Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 63:1983–1994CrossRefGoogle Scholar
  37. 37.
    Wang Q, Cobo-Stark P, Patel V, Somlo S, Han PL, Igarashi P (2018) Adenylyl cyclase 5 deficiency reduces renal cyclic AMP and cyst growth in an orthologous mouse model of polycystic kidney disease. Kidney Int 93:403–415CrossRefGoogle Scholar
  38. 38.
    Hopp K, Hommerding CJ, Wang X, Ye H, Harris PC, Torres VE (2015) Tolvaptan plus pasireotide shows enhanced efficacy in a PKD1 model. J Am Soc Nephrol 26:39–47CrossRefGoogle Scholar
  39. 39.
    Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E et al (2012) Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med 367:2407–2418CrossRefGoogle Scholar
  40. 40.
    Reif GA, Yamaguchi T, Nivens E, Fujiki H, Pinto CS, Wallace DP (2011) Tolvaptan inhibits ERK-dependent cell proliferation, Cl(−) secretion, and in vitro cyst growth of human ADPKD cells stimulated by vasopressin. Am J Physiol Renal Physiol 301:F1005–F1013CrossRefGoogle Scholar
  41. 41.
    Zhang MZ, Sanchez Lopez P, McKanna JA, Harris RC (2004) Regulation of cyclooxygenase expression by vasopressin in rat renal medulla. Endocrinology 145:1402–1409CrossRefGoogle Scholar
  42. 42.
    Hogan MC, Masyuk TV, Page LJ, Kubly VJ, Bergstralh EJ, Li X et al (2010) Randomized clinical trial of long-acting somatostatin for autosomal dominant polycystic kidney and liver disease. J Am Soc Nephrol 21:1052–1061CrossRefGoogle Scholar
  43. 43.
    Masyuk TV, Radtke BN, Stroope AJ, Banales JM, Gradilone SA, Huang B, Masyuk AI, Hogan MC, Torres VE, Larusso NF (2013) Pasireotide is more effective than octreotide in reducing hepatorenal cystogenesis in rodents with polycystic kidney and liver diseases. Hepatology 58:409–421CrossRefGoogle Scholar
  44. 44.
    Lakhia R, Hajarnis S, Williams D, Aboudehen K, Yheskel M, Xing C, Hatley ME, Torres VE, Wallace DP, Patel V (2016) MicroRNA-21 aggravates cyst growth in a model of polycystic kidney disease. J Am Soc Nephrol 27:2319–2330CrossRefGoogle Scholar
  45. 45.
    Belibi FA1, Reif G, Wallace DP, Yamaguchi T, Olsen L, Li H, Helmkamp GM Jr, Grantham JJ (2004) Cyclic AMP promotes growth and secretion in human polycystic kidney epithelial cells. Kidney Int 66:964–973CrossRefGoogle Scholar
  46. 46.
    Peacock O, Lee AC, Cameron F, Tarbox R, Vafadar-Isfahani N, Tufarelli C, Lund JN (2014) Inflammation and MiR-21 pathways functionally interact to downregulate PDCD4 in colorectal cancer. PLoS One 9:e110267CrossRefGoogle Scholar
  47. 47.
    Wongrakpanich S, Wongrakpanich A, Melhado K, Rangaswami J (2018) A comprehensive review of non-steroidal anti-inflammatory drug use in the elderly. Aging Dis 9:143–150CrossRefGoogle Scholar
  48. 48.
    Laine L (2002) The gastrointestinal effects of nonselective NSAIDs and COX-2-selective inhibitors. Semin Arthritis Rheum 32:25–32CrossRefGoogle Scholar
  49. 49.
    Heleniak Z, Cieplińska M, Szychliński T, Rychter D, Jagodzińska K, Kłos A, Kuźmiuk I, Tylicka MJ, Tylicki L, Rutkowski B, Dębska-Ślizień A (2017) Nonsteroidal anti-inflammatory drug use in patients with chronic kidney disease. J Nephrol 30:781–786CrossRefGoogle Scholar
  50. 50.
    Ahmad SR, Kortepeter C, Brinker A, Chen M, Beitz J (2002) Renal failure associated with the use of celecoxib and rofecoxib. Drug Saf 25:537–544CrossRefGoogle Scholar
  51. 51.
    Warth LC, Noiseux NO, Hogue MH, Klaassen AL, Liu SS, Callaghan JJ (2016) Risk of acute kidney injury after primary and revision total hip arthroplasty and total knee arthroplasty using a multimodal approach to perioperative pain control including ketorolac and celecoxib. J Arthroplasty 31:253–255CrossRefGoogle Scholar
  52. 52.
    Fair DE, Ogborn MR, Weiler HA, Bankovic-Calic N, Nitschmann EP, Fitzpatrick-Wong SC, Aukema HM (2004) Dietary soy protein attenuates renal disease progression after 1 and 3 weeks in Han:SPRD-cy weanling rats. J Nutr 134:1504–1507CrossRefGoogle Scholar
  53. 53.
    Cahill LE, Peng CY, Bankovic-Calic N, Sankaran D, Ogborn MR, Aukema HM (2007) Dietary soya protein during pregnancy and lactation in rats with hereditary kidney disease attenuates disease progression in offspring. Br J Nutr 97:77–84CrossRefGoogle Scholar
  54. 54.
    Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661CrossRefGoogle Scholar
  55. 55.
    Jozsef L, Zouki C, Petasis NA, Serhan CN, Filep JG (2002) Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-kappa B and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc Natl Acad Sci USA 99:13266–13271CrossRefGoogle Scholar
  56. 56.
    Imig JD, Zhao X, Zaharis CZ, Olearczyk JJ, Pollock DM, Newman JW, Kim IH, Watanabe T, Hammock BD (2005) An orally active epoxide hydrolase inhibitor lowers blood pressure and provides renal protection in salt-sensitive hypertension. Hypertension 46:975–981CrossRefGoogle Scholar

Copyright information

© Italian Society of Nephrology 2019

Authors and Affiliations

  1. 1.Department of Food and Human Nutritional SciencesUniversity of ManitobaWinnipegCanada
  2. 2.Canadian Centre for Agri-Food Research in Health and MedicineSt. Boniface Hospital Albrechtsen Research CentreWinnipegCanada

Personalised recommendations