title: Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia-reperfusion in cyclosporine-immunosuppressed rats.
abstract: Ischemia-reperfusion and immunosuppressive therapy are a major cause of progressive renal failure after kidney transplantation. Recent studies have shown that administration of bone marrow mesenchymal stem cells (MSCs) improves kidney functional recovery in the acute phase of post ischemia-reperfusion  injury. In the present study, we used an original model of renal ischemia-reperfusion in immunosuppressed rats (NIRC) to investigate the effects of bone marrow MSCs on progression of chronic renal failure and the mechanisms potentially involved. Left renal ischemia-reperfusion (IR) was induced  in unilateral nephrectomized Lewis rats. After IR, rats were treated daily with cyclosporine (10 mg/kg SC) for 28 days. MSCs were injected into the kidney at day 7 after IR. At day 28 after IR, kidneys were removed for histomorphological, biochemical, and gene expression analysis. The effect  of conditioned media from MSCs on epithelial-mesenchymal transition was studied in vitro on HK2 cells. Our results show that, as compared to untreated NIRC rats, rats treated by intrarenal injection of MSCs 7 days after IR displayed improvement in renal function, reduction of interstitial  fibrosis, and decrease in chronic tubule injury. These effects were associated with a decrease in interstitial α-SMA accumulation and MMP2 activity, markers of fibroblast/fibroblast-like cell activation, and renal remodeling, respectively. Finally, experiments in vitro showed that MSC-conditioned  medium prevented epithelial-mesenchymal transition induced by TGF-β in HK2 cells. In conclusion, our results show that, in immunosuppressed animals, a single intrarenal administration of MSCs reduced renal fibrosis and promoted the recovery of renal function.
authors.affiliation: Inserm, UMR 1048, Institute of Metabolic and Cardiovascular Diseases (I2MC), Toulouse, France.
authors.forename: C
authors.initials: C
authors.lastname: Alfarano
authors.forename: C
authors.initials: C
authors.lastname: Roubeix
authors.forename: R
authors.initials: R
authors.lastname: Chaaya
authors.forename: C
authors.initials: C
authors.lastname: Ceccaldi
authors.forename: D
authors.initials: D
authors.lastname: Calise
authors.forename: C
authors.initials: C
authors.lastname: Mias
authors.forename: D
authors.initials: D
authors.lastname: Cussac
authors.forename: J L
authors.initials: JL
authors.lastname: Bascands
authors.forename: A
authors.initials: A
authors.lastname: Parini
mesh_terms: D000328:Adult; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008875:Middle Aged; D051381:Rats; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000601:surgery*
chemical_list: D007166:Immunosuppressive Agents; D016572:Cyclosporine