title: Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.
abstract: Autosomal recessive polycystic kidney disease is a truly catastrophic monogenetic disease, causing death and end stage renal disease in neonates and children. Using PCK female rats, an orthologous model of autosomal recessive polycystic kidney disease harboring mutant Pkhd1, we tested the hypothesis that intravenous renal cell transplantation with normal Sprague Dawley male kidney cells would improve the polycystic kidney disease phenotype. Cytotherapy with renal cells expressing wild type Pkhd1 and tubulogenic serum amyloid A1 had powerful and sustained beneficial effects on renal function and structure in the polycystic kidney disease model. Donor cell engraftment and both mutant and wild type Pkhd1 were found in treated but not control PCK kidneys 15 weeks after the final cell infusion. To examine the mechanisms of global protection with a small number of transplanted cells, we tested the hypothesis that exosomes derived from normal Sprague Dawley cells can limit the cystic phenotype of PCK recipient cells. We found that renal exosomes originating from normal Sprague Dawley cells carried and transferred wild type Pkhd1 mRNA to PCK cells in vivo and in vitro and restricted cyst formation by cultured PCK cells. The results indicate that transplantation with renal cells containing wild type Pkhd1 improves renal structure and function in autosomal recessive polycystic kidney disease and may provide an intra-renal supply of normal Pkhd1 mRNA.
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kelly
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Jizhong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Ling
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kamocka
authors.affiliation: Department of Anatomy, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Caroline
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of Anatomy, Indiana University School of Medicine, Indianapolis, IN, United States of America.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Gattone
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America; Department of Medicine, Veterans Affairs Medical Center, Indianapolis IN, United States of America.
authors.forename: Jesus H
authors.initials: JH
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D003560:Cysts / Q000378:metabolism; D004195:Disease Models, Animal; D055354:Exosomes; D005260:Female; D005838:Genotype; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007684:Kidney Tubules / Q000473:pathology*; D008099:Liver / Q000378:metabolism; D008297:Male; D010641:Phenotype; D017044:Polycystic Kidney, Autosomal Recessive / Q000378:metabolism* / Q000628:therapy*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D000685:Serum Amyloid A Protein / Q000378:metabolism
chemical_list: C479541:PKHD1 protein, rat; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D000685:Serum Amyloid A Protein