Moderate kidney disease inhibits atherosclerosis regression.
Chronic kidney disease (CKD) accelerates cardiovascular disease. The mechanisms that explain this independent, excess risk associated with CKD have not been fully elucidated.


OBJECTIVE
We propose that impaired regression of atherosclerosis in renal disease represents a novel risk factor for the heightened morbidity and mortality and resistance to treatment observed in patients with CKD.


RESULTS
Using a transplant model to study atherosclerosis regression, we transplanted atheromatous aortic segments generated in Apolipoprotein E knock-out (ApoE(-/-)) mice, into either control or moderately uremic, normolipidemic, wild-type mice. In non-uremic mice, lesions regressed 55%, whereas lesions in uremic mice increased in size by 17% (p<0.01 for control vs. uremic). The lesions in uremic mice were also characterized by a greater presence of macrophages (36,300 microm(2) vs. 12,600 microm(2), p<0.01). This finding was despite upregulation of chemokine receptor 7 (CCR7), normally a migration factor, in uremic lesion macrophages. Gene expression analysis of lesion macrophages showed relative down-regulation of serum response factor (SRF) target genes in the uremic group, consistent with impaired CCR7 signaling.


CONCLUSIONS
Moderate kidney disease inhibits regression of atherosclerosis in a mouse transplant model. This inhibition may be a result of impaired CCR7 signaling.
Ponda
Manish P
MP
Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY 10065, United States. mponda@rockefeller.edu
Barash
Irina
I
Feig
Jonathan E
JE
Fisher
Edward A
EA
Skolnik
Edward Y
EY
D000818:Animals; D001018:Aortic Diseases / Q000150:complications*; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000150:complications*; D002452:Cell Count; D004195:Disease Models, Animal; D015536:Down-Regulation; D007676:Kidney Failure, Chronic / Q000150:complications* / Q000473:pathology / Q000503:physiopathology; D008264:Macrophages / Q000737:chemistry / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054400:Receptors, CCR7 / Q000032:analysis; D026362:Serum Response Factor / Q000235:genetics
D001057:Apolipoproteins E; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D026362:Serum Response Factor