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Oxidized lipids, LOX‐1, and diabetic nephropathy
Author(s) -
Dominguez Jesus,
Kelly Katherine J.
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1153.6
Subject(s) - proinflammatory cytokine , medicine , endocrinology , diabetic nephropathy , inflammation , chemistry , dyslipidemia , diabetes mellitus
The early stages of nephropathy in obese, diabetic, dyslipidemic (ZS) rats are characterized by tubular lipid accumulation and pervasive inflammation. Our prior work has shown that these events are interrelated. We now tested the hypothesis that proximal tubules from ZS obese diabetic proteinuric rats in vivo, and cultured proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL), changed their normally quiescent epithelial phenotype into a proinflammatory phenotype. Urine of obese diabetic rats contained more lipid peroxides, and LOX‐1, a membrane receptor that internalizes oxidized lipids, was mobilized to luminal sites. Levels of the intercellular adhesion molecule‐1 (ICAM‐1) and focal adhesion kinase (FAK), which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in tubules of obese proteinuric rats. NRK52E cells exposed to oxLDL showed similar modifications, plus activation of MAPK enzymes and suppression of anti‐inflammatory transcription factor PPAR delta. In addition, oxLDL impaired epithelial barrier function. These alterations were prevented by an anti‐LOX‐1 antibody. The data support the concept that tubular LOX‐1 activation driven by lipid oxidants in the pre‐urine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants and abnormal tubular permeability may be partly responsible for the renal tubulo‐interstitial injury of obesity, diabetes and dyslipidemia.