Identification of stage-specific genes associated with lupus nephritis and response to remission induction in (NZB × NZW)F1 and NZM2410 mice.
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.


CONCLUSIONS
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.
Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, NY 11030.
Ramalingam
R
Bethunaickan
Department of Internal Medicine, Nephrology, University of Michigan, Ann Arbor, MI 48109.
Celine C
CC
Berthier
Department of Medicine, Mount Sinai Medical Center, New York, NY 10029.
Weijia
W
Zhang
Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, NY 11030.
Ridvan
R
Eksi
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
Hong-Dong
HD
Li
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109.
Yuanfang
Y
Guan
Department of Internal Medicine, Nephrology, University of Michigan, Ann Arbor, MI 48109.
Matthias
M
Kretzler
Center for Autoimmunity and Musculoskeletal Diseases, Feinstein Institute for Medical Research, Manhasset, New York, NY 11030.
Anne
A
Davidson
D000818:Animals; D018450:Disease Progression; D005260:Female; D008181:Lupus Nephritis / Q000235:genetics*; D051379:Mice; D008814:Mice, Inbred NZB; D012074:Remission Induction; D059467:Transcriptome