Journal
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volume 304, Issue 2, Pages F168-F176Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajprenal.00129.2012
Keywords
glomerulonephritis; soluble epoxide hydrolase; proteinuria; inflammation; epithelial-mesenchymal transition
Categories
Funding
- Major National Basic Research Grant of China [2010CB912504, 2012CB517504]
- National Natural Science Foundation of China [30971063, 81130002, 81070213]
- 111 plan of China
- National Institute of Environmental Health Sciences, NIH [RO1 HL059699, RO1 ES02710]
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Wang Q, Pang W, Cui Z, Shi J, Liu Y, Liu B, Zhou Y, Guan Y, Hammock BD, Wang Y, Zhu Y. Upregulation of soluble epoxide hydrolase in proximal tubular cells mediated proteinuria-induced renal damage. Am J Physiol Renal Physiol 304: F168-F176, 2013. First published November 14, 2012; doi:10.1152/ajprenal.00129.2012.-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 alpha-smooth muscle actin (alpha-SMA) and decreased Ecadherin. 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 alpha-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.
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