Selective depletion of fibroblasts preserves morphology and the functional integrity of peritoneum in transgenic mice with peritoneal fibrosing syndrome.
BACKGROUND
A peritoneal fibrosing syndrome (PFS) can progressively reduce peritoneal ultrafiltration during chronic peritoneal dialysis in patients with renal failure. The pathogenesis of PFS is unclear and the role of peritoneal fibroblasts has not been evaluated experimentally.


METHODS
We followed the fate of fibroblasts producing PFS in a mouse model using fibroblast-specific protein 1 (FSP1) as a marker. PFS was induced by daily peritoneal infusions of chlorhexidine gluconate (CHG) saline into transgenic mice expressing the thymidine kinase (Delta tk) gene under the control of the FSP1 promoter (FSP1.Delta tk mice). To demonstrate the role of fibroblasts in PFS, we treated these FSP1.Delta tk mice with a nucleoside analogue to induce DNA chain termination and fibroblast death.


RESULTS
Mice receiving peritoneal infusions of CHG saline every other day for 2 weeks developed increasing numbers of FSP1+ fibroblasts in the subserosal layers of the visceral peritoneum. Mac-3+ monocytes (macrophages) subsequently accumulated over the next 2 weeks in association with increased deposition of type I collagen and increased endothelial vascularity (CD31+) in these subserosal tissues. Since these peritoneal fibroblasts expressed monocyte chemoattractant protein-1 (MCP-1), heat shock protein 47 (HSP47), and vascular endothelial growth factor (VEGF), we suspect they were partially responsible for macrophage recruitment, matrix production, and the neoangiogenesis in the subserosal tissue. Treatment of PFS in FSP1.Delta tk transgenic mice with a nucleoside analogue selectively reduced the numbers of peritoneal fibroblasts and attenuated the attendant changes in peritoneal histology. Rescuing the peritoneal membrane from chronic thickening and neoangiogenesis by reducing the number of fibroblasts also preserved ultrafiltration.


CONCLUSIONS
Peritoneal fibroblasts play a pivotal role in PFS, and their deletion using a fibroblasts-specific transgene was effective in preventing peritoneal fibrogenesis.
Okada
Hirokazu
H
Department of Nephrology, Saitama Medical College, Saitama, Japan. hirookda@saitama-med.ac.jp
Inoue
Tsutomu
T
Kanno
Yoshihiko
Y
Kobayashi
Tatsuya
T
Watanabe
Yusuke
Y
Ban
Shinichi
S
Neilson
Eric G
EG
Suzuki
Hiromichi
H
D000818:Animals; D015415:Biomarkers; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D005355:Fibrosis; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010530:Peritoneal Dialysis / Q000009:adverse effects*; D010537:Peritoneum / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D000071999:S100 Calcium-Binding Protein A4; D009418:S100 Proteins; C470944:S100a4 protein, mouse