Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model.
Mesenchymal stem cells (MSCs) have regenerative properties in acute kidney injury, but their role in chronic kidney diseases is still unknown. More specifically, it is not known whether MSCs halt fibrosis. The purpose of this work was to investigate the role of MSCs in fibrogenesis using a model of chronic renal failure. MSCs were obtained from the tibias and femurs of male Wistar-EPM rats. Female Wistar rats were subjected to the remnant model, and 2|x|10(5) MSCs were intravenously administrated to each rat every other week for 8 weeks or only once and followed for 12 weeks. SRY gene expression was observed in female rats treated with male MSCs, and immune localization of CD73(+)CD90(+) cells at 8 weeks was also assessed. Serum and urine analyses showed an amelioration of functional parameters in MSC-treated animals at 8 weeks, but not at 12 weeks. Masson's trichrome and Sirius red staining demonstrated reduced levels of fibrosis in MSC-treated animals. These results were corroborated by reduced vimentin, type I collagen, transforming growth factor beta, fibroblast specific protein 1 (FSP-1), monocyte chemoattractant protein 1, and Smad3 mRNA expression and alpha smooth muscle actin and FSP-1 protein expression. Renal interleukin (IL)-6 and tumor necrosis factor alpha mRNA expression levels were significantly decreased after MSC treatment, whereas IL-4 and IL-10 expression levels were increased. All serum cytokine expression levels were decreased in MSC-treated animals. Taken together, these results suggested that MSC therapy can indeed modulate the inflammatory response that follows the initial phase of a chronic renal injury. The immunosuppressive and remodeling properties of MSCs may be involved in the decreased fibrosis in the kidney.
Semedo
Patricia
P
Nephrology Division, Medicine Department, Federal University of São Paulo, 05508-900 São Paulo, SP, Brazil.
Correa-Costa
Matheus
M
Antonio Cenedeze
Marcos
M
Maria Avancini Costa Malheiros
Denise
D
Antonia dos Reis
Marlene
M
Shimizu
Maria Heloisa
MH
Seguro
Antonio Carlos
AC
Pacheco-Silva
Alvaro
A
Saraiva Camara
Niels Olsen
NO
D000818:Animals; D002454:Cell Differentiation; D065150:Cellular Reprogramming; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000601:surgery; D005786:Gene Expression Regulation; D007674:Kidney Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines