Bone marrow-derived mesenchymal stem cells repaired but did not prevent gentamicin-induced acute kidney injury through paracrine effects in rats

• Published in: PloS one 2012-09, Vol.7 (9), p.e44092
• Main Authors: Reis, Luciana A, Borges, Fernanda T, Simões, Manuel J, Borges, Andrea A, Sinigaglia-Coimbra, Rita, Schor, Nestor
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - blood; Acute Kidney Injury - chemically induced; Acute Kidney Injury - prevention & control; Acute Kidney Injury - therapy; Adipocytes; Animals; Apoptosis; Biology; Bone marrow; Bone Marrow Cells - cytology; Cancer; Cell proliferation; Conditioning; Creatinine; Culture Media, Conditioned - pharmacology; Cytokines; Cytokines - blood; Docking; Exosomes; Exosomes - metabolism; Exosomes - ultrastructure; Female; Flow Cytometry; Fluorescent Antibody Technique; Gentamicin; Gentamicins - adverse effects; Hypotheses; Inflammation; Injury analysis; Injury prevention; Ischemia; Kidney - drug effects; Kidney - pathology; Kidneys; Male; Medical research; Medicine; Mesenchymal Stem Cell Transplantation; Mesenchymal stem cells; Mesenchymal Stem Cells - cytology; Mesenchymal Stem Cells - drug effects; Mesenchymal Stem Cells - metabolism; Mesenchyme; Microscopy; Nephrology; Paracrine Communication - drug effects; Paracrine signalling; Prevention; Rats; Rats, Wistar; Ribonuclease; Ribonucleic acid; RNA; Rodents; Stem cell transplantation; Stem cells; Transplantation; Trypsin; Urea; Wound Healing - drug effects; Y Chromosomes
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0044092

This study evaluated the effects of bone marrow-derived mesenchymal stem cells (BMSCs) or their conditioned medium (CM) on the repair and prevention of Acute Kidney Injury (AKI) induced by gentamicin (G). Animals received daily injections of G up to 20 days. On the 10(th) day, injections of BMSCs, CM, CM+trypsin, CM+RNase or exosome-like microvesicles extracted from the CM were administered. In the prevention groups, the animals received the BMSCs 24 h before or on the 5(th) day of G treatment. Creatinine (Cr), urea (U), FENa and cytokines were quantified. The kidneys were evaluated using hematoxylin/eosin staining and immunohystochemistry. The levels of Cr, U and FENa increased during all the periods of G treatment. The BMSC transplantation, its CM or exosome injections inhibited the increase in Cr, U, FENa, necrosis, apoptosis and also increased cell proliferation. The pro-inflammatory cytokines decreased while the anti-inflammatory cytokines increased compared to G. When the CM or its exosomes were incubated with RNase (but not trypsin), these effects were blunted. The Y chromosome was not observed in the 24-h prevention group, but it persisted in the kidney for all of the periods analyzed, suggesting that the injury is necessary for the docking and maintenance of BMSCs in the kidney. In conclusion, the BMSCs and CM minimized the G-induced renal damage through paracrine effects, most likely through the RNA carried by the exosome-like microvesicles. The use of the CM from BMSCs can be a potential therapeutic tool for this type of nephrotoxicity, allowing for the avoidance of cell transplantations.