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Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

Kelly KJ, Zhang J, Han L, Kamocka M, Miller C, Gattone VH, Dominguez JH - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

Histology.Representative trichrome stained sections (resulting in blue labeling of fibrous tissue) of glomeruli (glom), cortex and medulla in each of the 6 groups are presented. Quantification of glomerulosclerosis (in a total of 5602 glomeruli) and peritubular fibrosis (in 4249 microscope fields) is presented in the graphs. GLOM, glomeruli; NO, no cells; CTRL, control; *p<0.05 vs no cell group; ‡p<0.05 vs no cell/ischemia group; §p<0.05 vs control cell group; #p<0.05 control cell/ischemia group
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pone.0131677.g006: Histology.Representative trichrome stained sections (resulting in blue labeling of fibrous tissue) of glomeruli (glom), cortex and medulla in each of the 6 groups are presented. Quantification of glomerulosclerosis (in a total of 5602 glomeruli) and peritubular fibrosis (in 4249 microscope fields) is presented in the graphs. GLOM, glomeruli; NO, no cells; CTRL, control; *p<0.05 vs no cell group; ‡p<0.05 vs no cell/ischemia group; §p<0.05 vs control cell group; #p<0.05 control cell/ischemia group

Mentions: Fibrosis is a significant contributor to decreased function in PKD [26]. In addition to improvements in function and total cyst volume, decreases in both peritubular fibrosis and glomerulosclerosis were also observed in treated kidneys. SAA+ cells results in larger improvements in fibrosis than SAA- cells (Fig 6).


Improved Structure and Function in Autosomal Recessive Polycystic Rat Kidneys with Renal Tubular Cell Therapy.

Kelly KJ, Zhang J, Han L, Kamocka M, Miller C, Gattone VH, Dominguez JH - PLoS ONE (2015)

Histology.Representative trichrome stained sections (resulting in blue labeling of fibrous tissue) of glomeruli (glom), cortex and medulla in each of the 6 groups are presented. Quantification of glomerulosclerosis (in a total of 5602 glomeruli) and peritubular fibrosis (in 4249 microscope fields) is presented in the graphs. GLOM, glomeruli; NO, no cells; CTRL, control; *p<0.05 vs no cell group; ‡p<0.05 vs no cell/ischemia group; §p<0.05 vs control cell group; #p<0.05 control cell/ischemia group
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4489886&req=5

pone.0131677.g006: Histology.Representative trichrome stained sections (resulting in blue labeling of fibrous tissue) of glomeruli (glom), cortex and medulla in each of the 6 groups are presented. Quantification of glomerulosclerosis (in a total of 5602 glomeruli) and peritubular fibrosis (in 4249 microscope fields) is presented in the graphs. GLOM, glomeruli; NO, no cells; CTRL, control; *p<0.05 vs no cell group; ‡p<0.05 vs no cell/ischemia group; §p<0.05 vs control cell group; #p<0.05 control cell/ischemia group
Mentions: Fibrosis is a significant contributor to decreased function in PKD [26]. In addition to improvements in function and total cyst volume, decreases in both peritubular fibrosis and glomerulosclerosis were also observed in treated kidneys. SAA+ cells results in larger improvements in fibrosis than SAA- cells (Fig 6).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus