TY - JOUR
T1 - Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice
AU - Bethunaickan, Ramalingam
AU - Berthier, Celine C.
AU - Zhang, Weijia
AU - Eksi, Ridvan
AU - Li, Hong Dong
AU - Guan, Yuanfang
AU - Kretzler, Matthias
AU - Davidson, Anne
PY - 2014/8
Y1 - 2014/8
N2 - Objective To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission, and relapse of nephritis in murine lupus models using transcriptome analysis. Methods Kidneys from (NZB × NZW)F1 (NZB/NZW) and NZM2410 mice were harvested at intervals during the disease course or after remission induction. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time polymerase chain reaction (PCR) analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire data set using singular value decomposition and self-organizing maps were performed. Results Few changes in the renal molecular profile were detected in prenephritic kidneys, but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling, and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all, of the inflammatory changes, and progression toward relapse was associated with recurrence of inflammation, mitochondrial dysfunction, and metabolic stress signatures. Conclusion Immune cell infiltration and activation is associated with proteinuria onset and is reversed by immunosuppressive therapy, but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy for lupus nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in the kidneys of lupus patients suggests potential new biomarkers and therapeutic targets.
AB - Objective To elucidate the molecular mechanisms involved in renal inflammation during the progression, remission, and relapse of nephritis in murine lupus models using transcriptome analysis. Methods Kidneys from (NZB × NZW)F1 (NZB/NZW) and NZM2410 mice were harvested at intervals during the disease course or after remission induction. Genome-wide expression profiles were obtained from microarray analysis of perfused kidneys. Real-time polymerase chain reaction (PCR) analysis for selected genes was used to validate the microarray data. Comparisons between groups using SAM, and unbiased analysis of the entire data set using singular value decomposition and self-organizing maps were performed. Results Few changes in the renal molecular profile were detected in prenephritic kidneys, but a significant shift in gene expression, reflecting inflammatory cell infiltration and complement activation, occurred at proteinuria onset. Subsequent changes in gene expression predominantly affected mitochondrial dysfunction and metabolic stress pathways. Endothelial cell activation, tissue remodeling, and tubular damage were the major pathways associated with loss of renal function. Remission induction reversed most, but not all, of the inflammatory changes, and progression toward relapse was associated with recurrence of inflammation, mitochondrial dysfunction, and metabolic stress signatures. Conclusion Immune cell infiltration and activation is associated with proteinuria onset and is reversed by immunosuppressive therapy, but disease progression is associated with renal hypoxia and metabolic stress. Optimal therapy for lupus nephritis may therefore need to target both immune and nonimmune disease mechanisms. In addition, the overlap of a substantial subset of molecular markers with those expressed in the kidneys of lupus patients suggests potential new biomarkers and therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=84905037992&partnerID=8YFLogxK
U2 - 10.1002/art.38679
DO - 10.1002/art.38679
M3 - Article
C2 - 24757019
AN - SCOPUS:84905037992
SN - 2326-5191
VL - 66
SP - 2246
EP - 2258
JO - Arthritis and Rheumatology
JF - Arthritis and Rheumatology
IS - 8
ER -