LOX-1 and inflammation: a new mechanism for renal injury in obesity and diabetes.
The early nephropathy in obese, diabetic, dyslipidemic (ZS) rats is characterized by tubular lipid accumulation and pervasive inflammation, two critically interrelated events. We now tested the hypothesis that proximal tubules from ZS obese diabetic rats in vivo, and proximal tubule cells (NRK52E) exposed to oxidized LDL (oxLDL) in vitro, change 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 ICAM-1 and focal adhesion kinase, which participate in leukocyte migration and epithelial dedifferentiation, respectively, were also upregulated in tubules. NRK52E cells exposed to oxLDL showed similar modifications, plus suppression of anti-inflammatory transcription factor peroxisome proliferator-activated receptor-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 preurine fluid is critical in the inflammatory changes. We suggest that luminal lipid oxidants and abnormal tubular permeability may be partly responsible for the renal tubulointerstitial injury of obesity, diabetes, and dyslipidemia.
Kelly
Katherine J
KJ
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Wu
Pengfei
P
Patterson
Carolyn E
CE
Temm
Constance
C
Dominguez
Jesus H
JH
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D002448:Cell Adhesion / Q000502:physiology; D002460:Cell Line; D002463:Cell Membrane Permeability / Q000502:physiology; D003928:Diabetic Nephropathies / Q000150:complications / Q000473:pathology*; D017097:Electric Impedance; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000235:genetics / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007674:Kidney Diseases / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D007684:Kidney Tubules / Q000473:pathology; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000473:pathology*; D047494:PPAR delta / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011973:Receptors, LDL / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000502:physiology*; D014018:Tissue Distribution; D015854:Up-Regulation / Q000502:physiology
C495136:OLR1 protein, rat; D047494:PPAR delta; D011973:Receptors, LDL; D051127:Scavenger Receptors, Class E; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases