Kallikrein transduced mesenchymal stem cells protect against anti-GBM disease and lupus nephritis by ameliorating inflammation and oxidative stress.
Previously we have shown that kallikreins (klks) play a renoprotective role in nephrotoxic serum induced nephritis. In this study, we have used mesenchymal stem cells (MSCs) as vehicles to deliver klks into the injured kidneys and have measured their therapeutic effect on experimental antibody induced nephritis and lupus nephritis. Human KLK-1 (hKLK1) gene was transduced into murine MSCs using a retroviral vector to generate a stable cell line, hKLK1-MSC, expressing high levels of hKLK1. 129/svj mice subjected to anti-GBM induced nephritis were transplanted with 10(6) hKLK1-MSCs and hKLK1 expression was confirmed in the kidneys. Compared with vector-MSCs injected mice, the hKLK1-MSCs treated mice showed significantly reduced proteinuria, blood urea nitrogen (BUN) and ameliorated renal pathology. Using the same strategy, we treated lupus-prone B6.Sle1.Sle3 bicongenic mice with hKLK1-MSCs and demonstrated that hKLK1-MSCs delivery also attenuated lupus nephritis. Mechanistically, hKLK1-MSCs reduced macrophage and T-lymphocyte infiltration into the kidney by suppressing the expression of inflammation cytokines. Moreover, hKLK1 transduced MSCs were more resistant to oxidative stress-induced apoptosis. These findings advance genetically modified MSCs as potential gene delivery tools for targeting therapeutic agents to the kidneys in order to modulate inflammation and oxidative stress in lupus nephritis.
Department of Immunology and Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
Yajuan
Y
Li
Indu
I
Raman
Yong
Y
Du
Mei
M
Yan
Soyoun
S
Min
Jichen
J
Yang
Xiangdong
X
Fang
Wei
W
Li
Jianxin
J
Lu
Xin J
XJ
Zhou
Chandra
C
Mohan
Quan-Zhen
QZ
Li
D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000097:blood / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D018925:Chemokines / Q000097:blood / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000097:blood / Q000473:pathology*; D007610:Kallikreins / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000097:blood / Q000473:pathology / Q000517:prevention & control / Q000628:therapy*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014161:Transduction, Genetic
D018925:Chemokines; D006861:Hydrogen Peroxide; D007610:Kallikreins