Abstract
BackgroundLipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood.MethodsTo clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics was performed to reveal lipid profiles of CKD kidneys.ResultsIn 5/6 Nx kidneys, both mRNA and protein levels of Alox15 were higher when compared with those in sham kidneys. With respect to in situ hybridization, the mRNA level of Alox15 was higher in renal tubules of 5/6 Nx kidneys. To examine the role of Alox15 in CKD pathogenesis, we performed 5/6 Nx on Alox15−/− mice. Alox15−/− CKD mice exhibited better renal functions than wild-type mice. Interstitial fibrosis was also inhibited in Alox15−/− CKD mice. Mediator lipidomics revealed that Alox15−/− CKD mouse kidneys had significantly higher levels of PGD2 than the control. To investigate the effects of PGD2 on renal fibrosis, we administered PGD2 to TGF-β1-stimulated NRK-52E cells and HK-2 cells, which lead to a dose-dependent suppression of type I collagen and αSMA in both cell lines.ConclusionIncreased PGD2 in Alox15−/− CKD mouse kidneys could inhibit fibrosis, thereby resulting in CKD improvement. Thus, Alox15 inhibition and PGD2 administration may be novel therapeutic targets for CKD.
Highlights
Polyunsaturated fatty acids (PUFA) and their metabolites are linked to inflammation and its resolution in several organs [1]
This study revealed that both of the transcription and protein expression levels of Alox15 were increased in chronic kidney disease (CKD) kidneys, and Alox15−/− mice demonstrated improved kidney dysfunction and fibrosis in the CKD model
To determine which cell types had increased Alox15 protein level in the CKD kidney, we examined the localization of Alox15 mRNA by in situ hybridization
Summary
Polyunsaturated fatty acids (PUFA) and their metabolites are linked to inflammation and its resolution in several organs [1]. Biosynthesis of oxylipins is mediated by several enzymes, such as lipoxygenase (LOX), cyclooxygenase (COX) and cytochrome P450 (CYP) [3]. These enzymes produce several lipid metabolites, such as prostaglandins, leukotrienes, and lipoxins, which are all heavily involved in the regulation of inflammation [1, 4]. Lipid-metabolizing enzymes and their metabolites affect inflammation and fibrosis, but their roles in chronic kidney disease (CKD) have not been completely understood. Methods To clarify their role in CKD, we measured the mRNA levels of major lipid-metabolizing enzymes in 5/6 nephrectomized (Nx) kidneys of C57BL/6 J mice. Mediator lipidomics revealed that Alox15−/− CKD mouse kidneys had significantly higher levels of PGD2 than the control. Alox inhibition and PGD2 administration may be novel therapeutic targets for CKD
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