Cyclooxygenase (COX) Derived Oxylipins are Elevated in Models of Polycystic Kidney Disease, Indicating Potential for COX Inhibition to Treat Disease
Authors: Monirujjaman Md , Devassy JG , Yamaguchi T , Gabbs Melissa , Winter Tanja , Ravandi A , Aukema HM 
Published: November 2023

Background

Oxylipins (e.g. prostaglandins, leukotrienes) are bioactive lipids formed via oxidative metabolism of polyunsaturated fatty acids. The oxylipin profile is altered in the Han:SPRD‐Cy rat and the pcy mouse, both models of nephronophthisis, a rare type of renal cyst disease. In these models, oxylipins formed via the cyclooxygenase (COX) pathway are elevated, while those produced via the lipoxygenase (LOX) and cytochrome P450 (CYP) pathways are reduced. Further, inhibition of COX oxylipin formation reduces disease progression in Han:SPRD‐Cy rat, suggesting its potential for the treatment of these rare disorders. Polycystic kidney diseases (PKD) are more common forms of renal cyst diseases: autosomal dominant PKD (ADPKD) affects 1:400 to 1:1000 individuals and autosomal recessive PKD (ARPKD) affects 1:20,000 individuals. Since the oxylipin profile in PKD is not known, and since there are sex‐specific effects in PKD, the current studies were performed in orthologous models of PKD to determine whether oxylipins are altered in these more common disorders.

Methods

Mx1Cre+Pkd1flox/flox (Pkd1) mice and Pkd2WS25/−(Pkd2) mice are models of ADPKD, and PCK rats are a model of ARPKD. Four independent studies were performed. Male and female Pkd1 mice were injected with saline or polyinosinic polycytidylic acid (pI:pC) at 5 weeks (study#1) or 1 week (study#2) of age to induce disease, and kidneys obtained at 23 and 10 weeks of age, respectively. Kidneys from male and female Pkd2 mice (study#3) and male PCK rats (study#4) were obtained at 16 weeks of age. Over 100 oxylipins were analyzed by HPLC‐MS/MS and quantified using the stable isotope dilution technique.

Results

In Pkd1 mice induced at 5 weeks, renal levels of the COX metabolite prostaglandin (PG)E2 was 27% higher in diseased compared to normal kidneys, and in Pkd1 mice induced at 1 week, PGD2, PGE2 and 15k‐PGF2α were 24, 25 and 65% higher in diseased kidneys, respectively. In Pkd2 mice, PGD2 and PGF2α were elevated in diseased kidneys by 98 and 33%, respectively, and in the PCK rat, PGE2 and 6‐keto‐PGF1α (PGI2 metabolite) were elevated by 38 and 53%, respectively. COX oxylipins were higher in kidneys from females compared to males, but there were no sex differences in the disease effects on these oxylipins. In comparison to these consistently higher levels of COX derived oxylipins in diseased kidneys, the LOX and CYP derived oxylipin differences were fewer and less consistent.

Conclusions

COX oxylipins are elevated in all models of PKD examined, consistent with the findings in the Han:SPRD‐Cy rat and pcy mouse models of nephronophthisis. As COX inhibition slows disease progression in those rare renal cyst disorders, the current results in PKD models suggest that COX inhibition also may be effective in the more common PKD disorders, for which no effective therapies currently exist.

Support or Funding Information

Canadian Institutes of Health Research (CIHR)