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-kappa B 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.