Effects of sirolimus on mesangial cell cholesterol homeostasis: a novel mechanism for its action against lipid-mediated injury in renal allografts.
Lipoprotein abnormalities are present in a high proportion of renal transplant patients. It is accepted that dyslipidemia is associated with atherosclerosis and in the progression of renal disease. Lipid abnormalities may also play a significant role in the development of chronic allograft nephropathy. Sirolimus was found to have an antiatherosclerotic effect in the apolipoprotein E-knockout mice model of hyperlipidemia through its antiproliferative effects. As lipid-mediated renal injury is important in the pathogenesis of glomerulosclerosis which shares common pathogenic mechanisms with atherosclerosis, in this study we have tested the hypothesis that sirolimus prevents lipid-mediated renal injury through the modulation of cholesterol homeostasis of mesangial cells and its anti-inflammatory effects on macrophages. We demonstrated that sirolimus reduced lipid accumulation, as measured by oil red O staining in human mesangial cells (HMCs). Using real-time PCR, we screened the mRNA expression of lipoprotein receptors. Sirolimus significantly suppressed LDL and VLDL receptors and CD36 gene expression. It also increased cholesterol efflux from HMCs by increasing peroxisome proliferator-activated receptor-alpha (PPARalpha), PPARgamma, liver X receptor-alpha, and ATP binding cassette A1 (ABCA1) gene expression. Sirolimus overrode the suppression of cholesterol efflux and ABCA1 gene expression induced by the inflammatory cytokine IL-1beta. Furthermore, sirolimus significantly inhibited inflammatory cytokines IL-6 and TNF-alpha production in macrophages. These data suggest that sirolimus may prevent cellular cholesterol accumulation even in the presence of hyperlipidemia and inflammation, by regulating both cholesterol homeostasis and inflammatory responses.
Varghese
Zac
Z
Centre for Nephrology, Royal Free and University College Medical School, London NW3 2PF, UK. z.varghese@medsch.ucl.ac.uk
Fernando
Ray
R
Moorhead
John F
JF
Powis
Stephen H
SH
Ruan
Xiong Z
XZ
D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D005920:Glomerular Mesangium / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*
D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D002784:Cholesterol; D020123:Sirolimus