Retinoic acid treatment protects MRL/lpr lupus mice from the development of glomerular disease.
BACKGROUND
Retinoic acid (tRA) is an active metabolite of vitamin A with potent anti-inflammatory properties. We analyzed the effects of tRA on the development of lupus nephritis in MRL/lpr mice.


METHODS
MRL/lpr mice received chow supplemented with vehicle or tRA (daily 10 mg/kg) from 8 to 14 weeks until their sacrifice. MRL/wt mice served as an additional control.


RESULTS
tRA-treated MRL/lpr mice showed reduced lymphoadenopathy and splenomegaly as compared to vehicle-treated controls. Treatment reduced proteinuria to almost basal levels. Plasma IgG and anti-DNA antibodies increased comparably in both vehicle and tRA-treated mice. Vehicle-treated mice showed characteristic renal lesions. In contrast tRA-treated mice showed almost normal glomerular histology with a pronounced reduction in endocapillary cell proliferation. T-cell and macrophage infiltrates were reduced after tRA treatment within glomeruli and interstitium as compared to vehicle-treated animals. In spite of this, immune complex and complement deposition were comparable in both groups. Adoptively transferred T cells from vehicle-treated to tRA-treated MRL/lpr mice did not induce renal lesions or proteinuria. These beneficial effects of tRA treatment were associated with reduced renal expression of chemokines and inflammatory cytokines. Surprisingly, renal transforming growth factor-beta (TGF-beta) mRNA levels of tRA-treated mice were elevated, possibly indicating that TGF-beta acts as an anti-inflammatory signal in this lupus model.


CONCLUSIONS
tRA treatment reduces lymphoproliferation and glomerulonephritis in MRL/lpr mice. This occurs in spite of unaltered anti-DNA titers and glomerular immune complex deposition, and cannot be overcome by T-cell transfer from nephritic MRL/lpr mice.
Medizinische Poliklinik der Ludwig-Maximilians-Universität, München, Germany.
Guillermo
G
Pérez de Lema
Francisco Javier
FJ
Lucio-Cazaña
Ana
A
Molina
Bruno
B
Luckow
Holger
H
Schmid
Cor
C
de Wit
Victoria
V
Moreno-Manzano
Bernhard
B
Banas
Francisco
F
Mampaso
Detlef
D
Schlöndorff
D019264:Adoptive Transfer; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001835:Body Weight; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D007074:Immunoglobulin G / Q000097:blood; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008264:Macrophages / Q000166:cytology; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000166:cytology; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018925:Chemokines; D016207:Cytokines; D007074:Immunoglobulin G; D012333:RNA, Messenger; D014212:Tretinoin