Epoxyeicosatrienoic acids, hydrolyzed by soluble epoxide hydrolase (sEH), have multiple biological functions, including the regulation of vascular tone, renal tubular transport, and being anti-inflammatory. Inhibitors of sEH have been demonstrated to be antihypertensive and renal protective. To elucidate the role of sEH in glomerulonephritis, we first determined the expression of sEH in human kidney by examining biopsies from 153 patients with a variety of glomerulonephritis, including minimal-change, membranous, and IgA nephropathy. Immunohistochemical staining of frozen kidney biopsy samples revealed sEH preferentially expressed in the renal proximal tubular cells, and its expression increased in all patients with glomerulonephritis. The level of sEH in the cortex was positively correlated with proteinuria and negatively with serum albumin level. To investigate the role of sEH in proteinuria-induced renal damage, we incubated purified urine protein from patients with rat renal proximal tubular epithelial cells in vitro. The level of sEH was elevated, as were monocyte chemoattractant protein 1 and the process of tubular epithelial-to-mesenchymal transition, characterized with increased α-smooth muscle actin (α-SMA) and decreased E-cadherin. These effects were attenuated by administration of a potent sEH inhibitor and mimicked with adenovirus-mediated sEH overexpression. In adriamycin-induced nephropathic mice, sEH inhibitor did not ameliorate proteinuria or level of serum albumin but reduced the long-term elevated serum creatinine level, interstitial inflammation, fibrosis, and α-SMA expression. Thus upregulation of sEH in proximal tubular cells in chronic proteinuric kidney diseases may mediate proteinuria-induced renal damage; sEH inhibition by increasing renal eicosanoid levels could prevent the progression of chronic proteinuric kidney diseases.