Microarray analysis of glomerular gene expression in murine lupus nephritis.
To elucidate the molecular mechanism of glomerular events in lupus nephritis, we performed genome-wide mRNA expression analysis of glomeruli microdissected from lupus mice. MRL/lpr mice (12-week-old) were orally given vehicle or prednisolone (10 mg/kg per day) for 4 weeks. Renal histology of MRL/lpr mice revealed mesangial proliferative glomerulonephritis with cellular infiltration of macrophages, T cells, and neutrophils. We identified 567 up-regulated genes in MRL/lpr glomeruli compared to control congenic mice. Those included complement components, adhesion molecules, chemokines and their receptors, and molecules related to antigen presentation. Over 130 genes were considered preferentially or exclusively expressed in hematopoietic cell lineages possibly reflecting leukocytes accumulation. Of note is the finding that chemokines and chemokine receptors (CCL3, CCL4, CCL5, CXCL9, CXCL10, CXCL11, CXCL16, CCR5, CXCR3, and CXCR6) that are related to T helper 1 (Th1) cells accumulation were up-regulated concomitantly with increased expression of Ebi3, a subunit of IL-27 that plays a role in Th1 predominance. These changes were accompanied by increased mRNA expression of many genes that were inducible by Th1 cytokine interferon-gamma. Prednisolone markedly attenuated glomerular lesion and leukocyte influx parallel with the reduction of enhanced gene expression. The present study shows additional evidence supporting glomerular Th1 cells accumulation and their role. Our data also provide an important resource in seeking new therapeutic targets to lupus nephritis. Supplemental table: available only at http://dx.doi.org/10.1254/jphs.FP0071337.
Teramoto
Kae
K
Department of Applied Pharmacology and Therapeutics, Osaka City University Medical School, Asahimachi, Abeno-ku, Osaka, Japan.
Negoro
Nobuo
N
Kitamoto
Kouichirou
K
Iwai
Tomoaki
T
Iwao
Hiroshi
H
Okamura
Mikio
M
Miura
Katsuyuki
K
D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling / Q000379:methods*; D005938:Glucocorticoids / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D019463:Mice, Inbred MRL lpr; D042282:Microdissection; D020411:Oligonucleotide Array Sequence Analysis; D011239:Prednisolone / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D005938:Glucocorticoids; D012333:RNA, Messenger; D011239:Prednisolone