Kidney Week

Abstract: TH-PO681

COX2 Inhibition Slows Disease Progression and Improves the Altered Renal Lipid Mediator Profile in the Pkd2WS25/- Mouse Model of ADPKD

Session Information

• ADPKD: Genetic and Model Studies
  October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1001 Genetic Diseases of the Kidney: Cystic

Authors

• Monirujjaman, Md, University of Manitoba, Winnipeg, Manitoba, Canada

Md Monirujjaman,

• Aukema, Harold M., University of Manitoba, Winnipeg, Manitoba, Canada

Harold M. Aukema,

Background

Oxylipins are bioactive lipid mediators formed by oxygenation of polyunsaturated fatty acids via cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 (CYP) monooxygenases. We have shown that the earliest and most consistent alteration in the oxylipin profile in diverse models of cystic kidney diseases is increased levels of COX derived prostanoids. Several of these, such as PGD₂ and PGE₂ have been shown to mediate renal cyst formation by increasing intracellular cAMP production, a known abnormality in various forms of cystic kidney diseases. Further, inhibition of COX oxylipin formation reduces disease progression in a model of nephronophthisis, as well as in some non-cystic renal diseases. The present study was carried out to determine whether a selective COX2 inhibitor would reduce disease progression and ameliorate the altered renal oxylipin profile in the Pkd2 orthologous mouse model of autosomal dominant polycystic kidney disease 2 (ADPKD2).

Methods

Weanling male Pkd2^WS25/- mice were provided a standard laboratory rodent diet (AIN-93G) with or without 50 mg celecoxib per kg body weight per day, for 13 weeks. Renal cysts were analyzed histomorphometrically and serum BUN and creatinine levels were determined. Targeted lipidomic analysis of renal oxylipins was performed by HPLC-tandem mass spectrometry.

Results

Diseased animals had significant cyst involvement and reduced renal function as indicated by elevated BUN. Consistent with our previous studies, 8 of 11 COX derived prostanoids were higher in diseased kidneys. In addition, 24 of 33 LOX oxylipins and 7 of 16 CYP oxylipins were lower in diseased kidneys. Drug treatment reduced cyst area by 50%, cyst volume by 70%, and serum creatinine and BUN by 10-20%. With respect to lipid mediators, drug treatment reduced 5 of the 8 elevated COX derived prostanoids and increased 5 of the 24 LOX and 5 of the 7 CYP oxylipins that were reduced by disease.

Conclusion

Selective COX2 inhibition significantly ameliorates disease progression and improves renal function in Pkd2 mice. Further studies on dose, potential risks, and long-term effects of COX2 inhibition are needed to determine whether this is a viable therapeutic option to treat ADPKD.
Supported by the Natural Sciences and Engineering Research Council of Canada

Funding

• Veterans Affairs Support