Laser capture microdissection-microarray analysis of focal segmental glomerulosclerosis glomeruli.
Focal segmental glomerulosclerosis (FSGS) is a major cause of end-stage renal disease. In this report we used laser capture microdissection to purify diseased glomeruli, and microarrays to provide universal gene expression profiles. The results provide a deeper understanding of the molecular mechanisms of the disease process and suggest novel therapeutic strategies. Consistent with earlier studies, molecular markers of the differentiated podocyte, including WT1, nephrin, and VEGF, were dramatically downregulated in the diseased glomerulus. We also observed multiple changes consistent with increased TGF-beta signaling, including elevated expression of TGF-beta(2), TGF-beta(3), SMAD2, TGF-beta(1) receptor, and thrombospondin. In addition, there was relatively low level expression of Csf1r, a marker of macrophages, but elevated expression of the chemokines CXCL1, CXCL2, CCL3, and CXCL14. We also observed strongly upregulated expression of Sox9, a transcription factor that can drive a genetic program of chondrogenesis and fibrosis. Further, the gene with the greatest fold increase in expression in the diseased glomerulus was osteopontin, which has been previously strongly implicated in kidney fibrosis in the unilateral ureteral obstruction mouse model. These results confirm old findings, and indicate the involvement of new genetic pathways in the cause and progression of FSGS.
Bennett
Michael R
MR
Division of Nephrology and Hypertension, Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Czech
Kimberly A
KA
Arend
Lois J
LJ
Witte
David P
DP
Devarajan
Prasad
P
Potter
S Steven
SS
D000293:Adolescent; D000328:Adult; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D005819:Genetic Markers; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D006801:Humans; D007150:Immunohistochemistry; D007834:Lasers; D008297:Male; D046228:Microarray Analysis; D042282:Microdissection / Q000379:methods*; D012720:Severity of Illness Index
D005819:Genetic Markers