N-Acetyl-Seryl-Aspartyl-Lysyl-Proline: mechanisms of renal protection in mouse model of systemic lupus erythematosus.
Systemic lupus erythematosus is an autoimmune disease characterized by the development of auto antibodies against a variety of self-antigens and deposition of immune complexes that lead to inflammation, fibrosis, and end-organ damage. Up to 60% of lupus patients develop nephritis and renal dysfunction leading to kidney failure. N-acetyl-seryl-aspartyl-lysyl-proline, i.e., Ac-SDKP, is a natural tetrapeptide that in hypertension prevents inflammation and fibrosis in heart, kidney, and vasculature. In experimental autoimmune myocarditis, Ac-SDKP prevents cardiac dysfunction by decreasing innate and adaptive immunity. It has also been reported that Ac-SDKP ameliorates lupus nephritis in mice. We hypothesize that Ac-SDKP prevents lupus nephritis in mice by decreasing complement C5-9, proinflammatory cytokines, and immune cell infiltration. Lupus mice treated with Ac-SDKP for 20 wk had significantly lower renal levels of macrophage and T cell infiltration and proinflammatory chemokine/cytokines. In addition, our data demonstrate for the first time that in lupus mouse Ac-SDKP prevented the increase in complement C5-9, RANTES, MCP-5, and ICAM-1 kidney expression and it prevented the decline of glomerular filtration rate. Ac-SDKP-treated lupus mice had a significant improvement in renal function and lower levels of glomerular damage. Ac-SDKP had no effect on the production of autoantibodies. The protective Ac-SDKP effect is most likely achieved by targeting the expression of proinflammatory chemokines/cytokines, ICAM-1, and immune cell infiltration in the kidney, either directly or via C5-9 proinflammatory arm of complement system.
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Tang-Dong
TD
Liao
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Pablo
P
Nakagawa
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Branislava
B
Janic
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Martin
M
D'Ambrosio
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Morel E
ME
Worou
Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
Edward L
EL
Peterson
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Nour-Eddine
NE
Rhaleb
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and.
Xiao-Ping
XP
Yang
Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, Michigan; and ocarret1@hfhs.org.
Oscar A
OA
Carretero
D000818:Animals; D002465:Cell Movement; D003165:Complement System Proteins / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000473:pathology
D016207:Cytokines; D009842:Oligopeptides; D018799:Intercellular Adhesion Molecule-1; D003165:Complement System Proteins; C058504:goralatide
Ac-SDKP; GFR; complement system proteins; inflammation; lupus nephritis; renal damage