Active maintenance of endothelial cells prevents kidney fibrosis

다국어 초록 (Multilingual Abstract)

Background: Soluble epoxide hydrolase (sEH) expressed by endothelial cells catalyzes the metabolism of epoxyeicosatrienoic acids (EETs), which are vasoactive agents.Methods: We used a unilateral ureteral obstruction mouse model of kidney fibrosis to determine whether inhibition of sEH activity reduces fibrosis, the final common pathway for chronic kidney disease. Results: sEH activity was inhibited by continuous release of the inhibitor 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) for 1 or 2 weeks. Treatment with AUDA significantly ameliorated tubulointerstitial fibrosis by reducing fibroblast mobilization and enhancing endothelial cell activity. In an in vitro model of endothelial-to-mesenchymal transition (EndMT) using human vascular endothelial cells (HUVECs), AUDA prevented the morphologic changes associated with EndMT and reduced expression of fibroblast-specific protein 1. Furthermore, HUVECs activated by AUDA prevented the epithelial-to-mesenchymal transition (EMT) of tubular epithelial cells in a co-culture system.Conclusion: Our findings suggest that regulation of sEH is a potential target for therapies aimed at delaying the progression of kidney fibrosis by inhibiting EndMT and EMT.

참고문헌 (Reference)

1 Zeisberg M, "The role of epithelial-to-mesenchymal transition in renal fibrosis" 82 : 175-181, 2004

2 Bohle A, "The consequences of tubulo-interstitial changes for renal function in glomerulopathies. A morphometric and cytological analysis" 186 : 135-144, 1990

3 Sanford LP, "TGFbeta2 knockout mice have multiple developmental defects that are non-overlapping with other TGFbeta knockout phenotypes" 24 : 2659-2670, 1997

4 Yang SH, "Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury" 22 : 1305-1314, 2011

5 Zhang W, "Soluble epoxide hydrolase:a novel therapeutic target in stroke" 27 : 1931-1940, 2007

6 Jung O, "Soluble epoxide hydrolase is a main effector of angiotensin II-induced hypertension" 45 : 759-765, 2005

7 Kompa AR, "Soluble epoxide hydrolase inhibition exerts beneficial anti-remodeling actions post-myocardial infarction" 167 : 210-219, 2013

8 Lee JP, "Soluble epoxide hydrolase activity determines the severity of ischemia-reperfusion injury in kidney" 7 : e37075-, 2012

9 Kang DH, "Role of the microvascular endothelium in progressive renal disease" 13 : 806-816, 2002

10 McPherson C, "Regulation of animal care and research? NIH’s opinion" 51 : 492-496, 1980

11 Kida Y, "Pivotal role of pericytes in kidney fibrosis" 38 : 467-473, 2011

12 Eddy AA, "Molecular basis of renal fibrosis" 15 : 290-301, 2000

13 Wynn TA, "Mechanisms of fibrosis: therapeutic translation for fibrotic disease" 18 : 1028-1040, 2012

14 Jung O, "Inhibition of the soluble epoxide hydrolase promotes albuminuria in mice with progressive renal disease" 5 : e11979-, 2010

15 Lee JP, "In vivo activity of epoxide hydrolase according to sequence variation affects the progression of human IgA nephropathy" 300 : F1283-F1290, 2011

16 Campbell WB, "Identification of epoxyeicosatrienoic acids as endotheliumderived hyperpolarizing factors" 78 : 415-423, 1996

17 Zeisberg EM, "Fibroblasts in kidney fibrosis emerge via endothelial-tomesenchymal transition" 19 : 2282-2287, 2008

18 Zeisberg M, "Fibroblasts emerge via epithelialmesenchymal transition in chronic kidney fibrosis" 13 : 6991-6998, 2008

19 Iwano M, "Evidence that fibroblasts derive from epithelium during tissue fibrosis" 110 : 341-350, 2002

20 Imig JD, "Epoxide hydrolase and epoxygenase metabolites as therapeutic targets for renal diseases" 289 : F496-F503, 2005

21 Zeisberg EM, "Endothelialto-mesenchymal transition contributes to cardiac fibrosis" 13 : 952-961, 2007

22 Li J, "Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice" 175 : 1380-1388, 2009

23 Zeisberg EM, "Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts" 67 : 10123-10128, 2007

24 Kim IH, "Design of bioavailable derivatives of 12-(3-adamantan-1-yl-ureido)dodecanoic acid, a potent inhibitor of the soluble epoxide hydrolase" 15 : 312-323, 2007

25 Chen G, "Cytochrome P450 epoxygenase CYP2J2 attenuates nephropathy in streptozotocininduced diabetic mice" 96 : 63-71, 2011

26 Medici D, "Conversion of vascular endothelial cells into multipotent stem-like cells" 16 : 1400-1406, 2010

27 Gadola L, "Calcium citrate ameliorates the progression of chronic renal injury" 65 : 1224-1230, 2004

28 Olearczyk JJ, "Administration of a substituted adamantyl urea inhibitor of soluble epoxide hydrolase protects the kidney from damage in hypertensive Goto-Kakizaki rats" 116 : 61-70, 2009