Atherogenic scavenger receptor modulation in the tubulointerstitium in response to chronic renal injury.
Oxidized low-density lipoproteins (oxLDL) and their scavenger receptor (SR) binding partners play a central role in atherosclerosis and by analogy may play a role in chronic kidney disease pathogenesis. The present study was designed to investigate in C57BL/6 mice the effects of hypercholesterolemia on renal injury severity and oxLDL generation after unilateral ureteral obstruction (UUO). The expression profiles of CD36, SR class AI/II (SR-A), lectin-like receptor for oxidized low-density lipoprotein-1 (Lox-1), and SR that binds phosphatidylserine and oxLDL (SR-PSOX/CXCL16) were examined. Four experimental groups were studied: sham and UUO male mice on either a high-fat Western diet or a control diet. Significantly more oxLDL accumulated in the tubulointerstitium of hypercholesterolemic mice compared with normocholesterolemic mice after 14 days of UUO (P < 0.01). Total kidney collagen was significantly higher in the obstructed kidneys of hypercholesterolemic mice compared with normocholesterolemic mice on day 14 (P < 0.01). After 14 days of obstruction, the number of interstitial F4/80+ macrophages and NF-kappaB activation increased in hypercholesterolemic mice compared with normocholesterolemic mice (P < 0.01). In normal kidneys, CD36, SR-A, Lox-1, and CXCL16 were primarily localized to renal tubular epithelia. After ureteral obstruction, CD36 increased at day 7; SR-A and Lox-1 progressively decreased in a time-dependent manner; and CXCL16 increased significantly with the onset of obstruction (P < 0.01). Strong tubular expression suggests that in addition to inflammatory interstitial cells, renal tubular scavenger receptors may help to orchestrate the inflammatory and fibrogenic pathways that are activated by oxLDL.
Okamura
Daryl M
DM
Children's Hospital and Regional Medical Center, Department of Pediatrics, University of Washington, 4800 Sand Point Way NE, Seattle WA 98015, USA. daryl.okamura@seattlechildrens.org
López-Guisa
Jesús M
JM
Koelsch
Katie
K
Collins
Sarah
S
Eddy
Allison A
AA
D000594:Amino Acid Oxidoreductases / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000503:physiopathology*; D015152:Blotting, Northern; D015153:Blotting, Western; D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004036:Diet, Atherogenic; D005355:Fibrosis / Q000473:pathology; D006937:Hypercholesterolemia / Q000097:blood; D007150:Immunohistochemistry; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000473:pathology*; D017463:Receptors, Complement 3b / Q000502:physiology; D051131:Receptors, Oxidized LDL / Q000378:metabolism; D051116:Receptors, Scavenger / Q000378:metabolism / Q000502:physiology*; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D014517:Ureteral Obstruction / Q000150:complications / Q000503:physiopathology
D000075743:Chemokine CXCL16; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; C498926:Cxcl16 protein, mouse; D008077:Lipoproteins, LDL; D016328:NF-kappa B; D017463:Receptors, Complement 3b; D051131:Receptors, Oxidized LDL; D051116:Receptors, Scavenger; D051117:Scavenger Receptors, Class A; D003094:Collagen; D000594:Amino Acid Oxidoreductases; C482019:Loxl1 protein, mouse