title: Mesenchymal stem cell therapy promotes renal repair by limiting glomerular podocyte and progenitor cell dysfunction in adriamycin-induced nephropathy.
abstract: We previously reported that in a model of spontaneously progressive glomerular injury with early podocyte loss, abnormal migration, and proliferation of glomerular parietal epithelial progenitor cells contributed to the formation of synechiae and crescentic lesions. Here we first investigated whether a similar sequence of events could be extended to rats with adriamycin (ADR)-induced nephropathy. As a second aim, the regenerative potential of therapy with bone marrow-derived mesenchymal stem cells (MSCs) on glomerular resident cells was evaluated. In ADR-treated rats, decrease of WT1(+) podocyte number due to apoptosis was associated with reduced glomerular expression of nephrin and CD2AP. As a consequence of podocyte injury, glomerular adhesions of the capillary tuft to the Bowman's capsule were observed, followed by crescent-like lesions and glomerulosclerosis. Cellular components of synechiae were either NCAM(+) parietal progenitor cells or nestin(+) podocytes. In ADR rats, repeated injections of MSCs limited podocyte loss and apoptosis and partially preserved nephrin and CD2AP. MSCs attenuated the formation of glomerular podocyte-parietal epithelial cell bridges and normalized the distribution of NCAM(+) progenitor cells along the Bowman's capsule, thereby reducing glomerulosclerosis. Finding that MSCs increased glomerular VEGF expression and limited microvascular rarefaction may explain the prosurvival effect by stem cell therapy. MSCs also displayed anti-inflammatory activity. Coculture of MSCs with ADR-damaged podocytes showed a functional role of stem cell-derived VEGF on prosurvival pathways. These data suggest that MSCs by virtue of their tropism for damaged kidney and ability to provide a local prosurvival environment may represent a useful strategy to preserve podocyte viability and reduce glomerular inflammation and sclerosis.
authors.affiliation: Mario Negri Institute for Pharmacological Research, Centro Anna Maria Astori, Science and Technology Park Km Rosso, Via Stezzano, 87-24126 Bergamo, Italy. carlamaria.zoja@marionegri.it
authors.forename: Carla
authors.initials: C
authors.lastname: Zoja
authors.forename: Pablo Bautista
authors.initials: PB
authors.lastname: Garcia
authors.forename: Cinzia
authors.initials: C
authors.lastname: Rota
authors.forename: Sara
authors.initials: S
authors.lastname: Conti
authors.forename: Elena
authors.initials: E
authors.lastname: Gagliardini
authors.forename: Daniela
authors.initials: D
authors.lastname: Corna
authors.forename: Cristina
authors.initials: C
authors.lastname: Zanchi
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.forename: Ariela
authors.initials: A
authors.lastname: Benigni
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Marina
authors.initials: M
authors.lastname: Morigi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002452:Cell Count; D002465:Cell Movement / Q000502:physiology; D018920:Coculture Techniques; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects; D007668:Kidney / Q000473:pathology / Q000502:physiology*; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D050199:Podocytes / Q000473:pathology / Q000502:physiology*; D051381:Rats; D011917:Rats, Inbred Lew; D012038:Regeneration / Q000502:physiology*; D013234:Stem Cells / Q000473:pathology / Q000502:physiology*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D042461:Vascular Endothelial Growth Factor A; C113267:nephrin; D004317:Doxorubicin