Epoxyeicosatrienoic acid activation moderates endothelial mesenchymal transition to reduce obstructive nephropathy

accounts for 45% of deaths around the world. Fibrosis is a key component in the progression of chronic kidney disease and involves the activation and accumulation of fibroblasts or myofibroblasts and the deposition of an extracellular matrix. Although it was previously thought that all collagen-producing fibroblasts originated solely from resident fibroblasts, other important sources of fibroblasts have been proposed, such as pericytes, circulating fibrocytes of bone marrow origin, and fibroblasts that originate from epithelial mesenchymal transition (EMT) and endothelial mesenchymal transition (EndMT) [1]. However, the contribution of these different sources to myofibroblast formation is under debate, and no consensus has been reached, particularly with respect to EMT and EndMT [1]. EndMT is a process by which endothelial cells acquire mesenchymal and stem cell-like phenotypic characteristics. Earlier reports indicated that 30% to 50% of renal interstitial myofibroblasts originated from the endothelium, although recent investigations demonstrate a lower contribution ranging from 10% to 23%. The presence of EndMT has also been confirmed in human patients with primary nephropathy (e.g., immunoglobulin A nephropathy) and secondary nephropathy (e.g., diabetic or lupus nephritis) due to double labeling of CD31 and α-SMA expression in the endothelium [2]. Several molecules, including activation of transforming growth factor (TGF) β and Notch and chronic activation of the Wnt-β-catenin pathway, are implicated in EndMT [3]. Inhibition of EndMT in kidney disease has been reported to ameliorate renal fibrosis. The use of the antidiabetic drug DPP4 inhibitor ameliorated kidney fibrosis in diabetic mice by inhibiting EndMT and restoring the microRNA mir-29 both in vivo and in vitro [4]. Yang et al [5] investigated the effects of inhibition of soluble epoxide hydrolase (sEH) on EndMT and renal fibrosis in the unilateral ureteral obstruction (UUO) model of chronic kidney disease. Epoxyeicosatrienoic acids (EETs) are arachidonic acid metabolites with biological effects, including vasodilation, angiogenesis, anti-inflammatory, anti-fibrotic, and anti-apoptotic functions. sEH-mediated hydrolysis of EETs to their corresponding and less-potent dihydroxyeicosatrienoic acids attenuates these effects. A role for EETs and sEH has been well established in renal fibrosis. The genetic or pharmacologic inhibition of sEH protects mice from renal interstitial fibrogenesis and inflammation after UUO. The mechanism by which sEH inhibition prevents injury has been proposed to be via EET activation, which may act through peroxisome proliferatoractivated receptor gamma to suppress TGF-β1 and TGFβ-independent mechanisms, including activation of nuclear factor-κB [6,7]. sEH inhibition was also shown to be renoprotective in an experimental model of adriamyEpoxyeicosatrienoic acid activation moderates endothelial mesenchymal transition to reduce obstructive nephropathy Babu J. Padanilam Departments of Cellular and Integrative Physiology and Internal Medicine, Section of Nephrology, University of Nebraska Medical Center, Omaha, NE, USA Editorial