Deletion of Alox15 improves kidney dysfunction and inhibits fibrosis by increased PGD2 in the kidney

Abstract

Background 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 was performed to reveal lipid profiles of CKD kidneys. Results In 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. Conclusion Increased 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.

Tissue transglutaminase exacerbates renal fibrosis via alternative activation of monocyte-derived macrophages

“…Macrophage infiltration and renal fibrosis were demonstrated to decrease in both ALOX15-knockout and inhibitor-treated mice but were increased in transgenic ALOX15overexpressing mice [41], and although that study did not include an in vitro analysis and the results from human macrophages, these results are consistent with our results obtained here. Additionally, studies of mice undergoing remnant nephrectomy, diabetic nephropathy, and sepsis-induced acute kidney injury had a similar profibrotic role of ALOX15 [52][53][54]. Consistent with these studies, the ALOX15 expression levels were found to be significantly higher in the kidneys of patients with advanced diabetic nephropathy, one of the main complications of diabetes [55].…”

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells

“…By analyzing the overlap between upregulated genes in nonstripped aortas from Ang II-treated TKO versus Cre mice with the downregulated transcripts in the anti-IL-9 mAb-treated TKO aortas, we identified potential genes involved with reversal of perivascular fibrosis, including Alox15 and Hp (Figure S12J). [47][48][49] We also compared the significant downregulated transcripts from the nonstripped aortic anti-IL-9 mAb treatment with the significant upregulated transcripts from aortic fibroblasts of Ang II treated TKO versus Cre mice to identity transcripts uniquely changed in fibroblasts after anti-IL-9 mAb rescue (Figure 8G). Indeed, the profibrotic genes Col8a1, Mmp2, Fmod, and Angptl1, which were identified as significantly increased in TKO aortas and in isolated fibroblasts by both bulk RNA seq and scRNA seq (Figure 7M), were all decreased after treatment with anti-IL-9 mAbs (Figure 8G).…”

Tissue transglutaminase exacerbates renal fibrosis via alternative activation of monocyte-derived macrophages

“…Macrophage in ltration and renal brosis were demonstrated to decrease in both ALOX15-knockout and inhibitor-treated mice but were increased in transgenic ALOX15overexpressing mice [42], and although that study did not include an in vitro analysis and the results from human macrophages, these results are consistent with our results obtained here. Additionally, studies of mice undergoing remnant nephrectomy, diabetic nephropathy, and sepsis-induced acute kidney injury had a similar pro brotic role of ALOX15 [50][51][52] . Consistent with these studies, the ALOX15 expression levels were found to be signi cantly higher in the kidneys of patients with advanced diabetic nephropathy, one of the main complications of diabetes 53 .…”