title: Human umbilical cord-derived mesenchymal stromal cells protect against premature renal senescence resulting from oxidative stress in rats with acute kidney injury.
abstract: Mesenchymal stromal cells (MSCs) represent an option for the treatment of acute kidney injury (AKI). It is known that young stem cells are better than are aged stem cells at reducing the incidence of the senescent phenotype in the kidneys. The objective of this study was to determine whether AKI leads to premature, stress-induced senescence, as well as whether human umbilical cord-derived MSCs (huMSCs) can prevent ischaemia/reperfusion injury (IRI)-induced renal senescence in rats.
  
  
  
  By clamping both renal arteries for 45 min, we induced IRI in male rats. Six hours later, some rats received 1 × 106huMSCs or human adipose-derived MSCs (aMSCs) intraperitoneally. Rats were euthanised and studied on post-IRI days 2, 7 and 49.
  
  
  
  On post-IRI day 2, the kidneys of huMSC-treated rats showed improved glomerular filtration, better tubular function and higher expression of aquaporin 2, as well as less macrophage infiltration. Senescence-related proteins (β-galactosidase, p21Waf1/Cip1, p16INK4aand transforming growth factor beta 1) and microRNAs (miR-29a and miR-34a) were overexpressed after IRI and subsequently downregulated by the treatment. The IRI-induced pro-oxidative state and reduction in Klotho expression were both reversed by the treatment. In comparison with huMSC treatment, the treatment with aMSCs improved renal function to a lesser degree, as well as resulting in a less pronounced increase in the renal expression of Klotho and manganese superoxide dismutase. Treatment with huMSCs ameliorated long-term kidney function after IRI, minimised renal fibrosis, decreased β-galactosidase expression and increased the expression of Klotho.
  
  
  
  Our data demonstrate that huMSCs attenuate the inflammatory and oxidative stress responses occurring in AKI, as well as reducing the expression of senescence-related proteins and microRNAs. Our findings broaden perspectives for the treatment of AKI.
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil. camila.eleuterio@usp.br.
authors.forename: Camila Eleuterio
authors.initials: CE
authors.lastname: Rodrigues
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: José Manuel Condor
authors.initials: JM
authors.lastname: Capcha
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: de Bragança
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Talita Rojas
authors.initials: TR
authors.lastname: Sanches
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Priscila Queiroz
authors.initials: PQ
authors.lastname: Gouveia
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Patrícia Aparecida Ferreira
authors.initials: PA
authors.lastname: de Oliveira
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Denise Maria Avancini Costa
authors.initials: DM
authors.lastname: Malheiros
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Rildo Aparecido
authors.initials: RA
authors.lastname: Volpini
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Mirela Aparecida Rodrigues
authors.initials: MA
authors.lastname: Santinho
authors.affiliation: Department of Internal Medicine, Division of Haematology, University of São Paulo at Ribeirão Preto School of Medicine, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, Brazil.
authors.forename: Bárbara Amélia Aparecida
authors.initials: BA
authors.lastname: Santana
authors.affiliation: Department of Internal Medicine, Division of Haematology, University of São Paulo at Ribeirão Preto School of Medicine, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, Brazil.
authors.forename: Rodrigo do Tocantins
authors.initials: RD
authors.lastname: Calado
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Irene de Lourdes
authors.initials: IL
authors.lastname: Noronha
authors.affiliation: Division of Nephrology, University of São Paulo School of Medicine, Av. Dr. Arnaldo, 455, 01246-903, São Paulo, Brazil.
authors.forename: Lúcia
authors.initials: L
authors.lastname: Andrade
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D051399:Aquaporin 2 / Q000235:genetics / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D005312:Fetal Blood / Q000166:cytology / Q000378:metabolism*; D005786:Gene Expression Regulation; D005919:Glomerular Filtration Rate; D005966:Glucuronidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D000090265:Klotho Proteins; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D011921:Rats, Inbred WKY; D012077:Renal Artery / Q000293:injuries; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: C496025:Aqp2 protein, rat; D051399:Aquaporin 2; C493958:Cdkn1a protein, rat; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C526366:MIRN29 microRNA, rat; C560944:MIRN34 microRNA, rat; D035683:MicroRNAs; D053773:Transforming Growth Factor beta1; D013482:Superoxide Dismutase; D001616:beta-Galactosidase; D005966:Glucuronidase; D000090265:Klotho Proteins
keywords: Acute kidney injury; Mesenchymal stromal cell; Senescence; Telomere; Umbilical cord; microRNA