Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model

Hayato Nishimura, Yasuhiko Ito, Masashi Mizuno, Akio Tanaka, Yoshiki Morita, Shoichi Maruyama, Yukio Yuzawa, Seiichi Matsuo

Research output: Contribution to journalArticle

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Abstract

Peritoneal fibrosis (PF) is an important complication of long-term peritoneal dialysis. Although mineralocorticoid and mineralocorticoid receptor (MR) have attracted increasing attention in the field of vascular injury, including the heart, kidney, and vessels, little is known about the role of mineralocorticoid in PF. This work was designed to explore the effects of MR blockade on PF. We developed a new model of PF in rats based on mechanical scraping of the peritoneum. This model is characterized by acute-phase inflammation (neutrophil and macrophage infiltration on days 0-3) and late-phase PF (α-smooth muscle actin-positive fibroblast infiltration, type III collagen accumulation, and neoangiogenesis on days 7-14). Peritoneal thickening peaked on day 14. MR was expressed in rat peritoneum and a rat fibroblast cell line. Expression of its effector kinase [serum- and glucocorticoid-induced kinase-1 (Sgk1)], transforming growth factor-β (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and CD31-positive vessels increased during the course of PF. Rats were treated with spironolactone, angiotensin receptor blockade (ARB), or angiotensin-converting enzyme inhibitor (ACEI)-ARB- spironolactone starting at 6 h after peritoneal scraping. All parameters, including peritoneal thickening, number of macrophages and CD31-positive vessels, and expression of monocyte chemoattractant protein-1, TGF-β, PAI-1, and Sgk1, were significantly suppressed by spironolactone (10 mg·kg-1 ·day-1). The effects of spironolactone (10 and 20 mg·kg-1 ·day-1) were very similar to those of triple blockade. ARB, but not ACEI, significantly reduced peritoneal thickening. Furthermore, peritoneal function assessed by peritoneal equilibration test was significantly improved by spironolactone. Our results suggest that MR is a potential target to prevent inflammation-induced PF in patients on peritoneal dialysis.

Original languageEnglish
JournalAmerican Journal of Physiology - Renal Physiology
Volume294
Issue number5
DOIs
Publication statusPublished - 01-05-2008
Externally publishedYes

Fingerprint

Peritoneal Fibrosis
Mineralocorticoid Receptors
Peritonitis
Spironolactone
Angiotensin Receptors
Mineralocorticoids
Phosphotransferases
Peritoneum
Plasminogen Activator Inhibitor 1
Transforming Growth Factors
Peritoneal Dialysis
Angiotensin-Converting Enzyme Inhibitors
Glucocorticoids
Fibroblasts
Macrophages
Inflammation
Collagen Type III
Neutrophil Infiltration
Chemokine CCL2
Vascular System Injuries

All Science Journal Classification (ASJC) codes

  • Physiology
  • Urology

Cite this

Nishimura, Hayato ; Ito, Yasuhiko ; Mizuno, Masashi ; Tanaka, Akio ; Morita, Yoshiki ; Maruyama, Shoichi ; Yuzawa, Yukio ; Matsuo, Seiichi. / Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model. In: American Journal of Physiology - Renal Physiology. 2008 ; Vol. 294, No. 5.
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abstract = "Peritoneal fibrosis (PF) is an important complication of long-term peritoneal dialysis. Although mineralocorticoid and mineralocorticoid receptor (MR) have attracted increasing attention in the field of vascular injury, including the heart, kidney, and vessels, little is known about the role of mineralocorticoid in PF. This work was designed to explore the effects of MR blockade on PF. We developed a new model of PF in rats based on mechanical scraping of the peritoneum. This model is characterized by acute-phase inflammation (neutrophil and macrophage infiltration on days 0-3) and late-phase PF (α-smooth muscle actin-positive fibroblast infiltration, type III collagen accumulation, and neoangiogenesis on days 7-14). Peritoneal thickening peaked on day 14. MR was expressed in rat peritoneum and a rat fibroblast cell line. Expression of its effector kinase [serum- and glucocorticoid-induced kinase-1 (Sgk1)], transforming growth factor-β (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and CD31-positive vessels increased during the course of PF. Rats were treated with spironolactone, angiotensin receptor blockade (ARB), or angiotensin-converting enzyme inhibitor (ACEI)-ARB- spironolactone starting at 6 h after peritoneal scraping. All parameters, including peritoneal thickening, number of macrophages and CD31-positive vessels, and expression of monocyte chemoattractant protein-1, TGF-β, PAI-1, and Sgk1, were significantly suppressed by spironolactone (10 mg·kg-1 ·day-1). The effects of spironolactone (10 and 20 mg·kg-1 ·day-1) were very similar to those of triple blockade. ARB, but not ACEI, significantly reduced peritoneal thickening. Furthermore, peritoneal function assessed by peritoneal equilibration test was significantly improved by spironolactone. Our results suggest that MR is a potential target to prevent inflammation-induced PF in patients on peritoneal dialysis.",
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Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model. / Nishimura, Hayato; Ito, Yasuhiko; Mizuno, Masashi; Tanaka, Akio; Morita, Yoshiki; Maruyama, Shoichi; Yuzawa, Yukio; Matsuo, Seiichi.

In: American Journal of Physiology - Renal Physiology, Vol. 294, No. 5, 01.05.2008.

Research output: Contribution to journalArticle

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AU - Nishimura, Hayato

AU - Ito, Yasuhiko

AU - Mizuno, Masashi

AU - Tanaka, Akio

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AU - Maruyama, Shoichi

AU - Yuzawa, Yukio

AU - Matsuo, Seiichi

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AB - Peritoneal fibrosis (PF) is an important complication of long-term peritoneal dialysis. Although mineralocorticoid and mineralocorticoid receptor (MR) have attracted increasing attention in the field of vascular injury, including the heart, kidney, and vessels, little is known about the role of mineralocorticoid in PF. This work was designed to explore the effects of MR blockade on PF. We developed a new model of PF in rats based on mechanical scraping of the peritoneum. This model is characterized by acute-phase inflammation (neutrophil and macrophage infiltration on days 0-3) and late-phase PF (α-smooth muscle actin-positive fibroblast infiltration, type III collagen accumulation, and neoangiogenesis on days 7-14). Peritoneal thickening peaked on day 14. MR was expressed in rat peritoneum and a rat fibroblast cell line. Expression of its effector kinase [serum- and glucocorticoid-induced kinase-1 (Sgk1)], transforming growth factor-β (TGF-β), plasminogen activator inhibitor-1 (PAI-1), and CD31-positive vessels increased during the course of PF. Rats were treated with spironolactone, angiotensin receptor blockade (ARB), or angiotensin-converting enzyme inhibitor (ACEI)-ARB- spironolactone starting at 6 h after peritoneal scraping. All parameters, including peritoneal thickening, number of macrophages and CD31-positive vessels, and expression of monocyte chemoattractant protein-1, TGF-β, PAI-1, and Sgk1, were significantly suppressed by spironolactone (10 mg·kg-1 ·day-1). The effects of spironolactone (10 and 20 mg·kg-1 ·day-1) were very similar to those of triple blockade. ARB, but not ACEI, significantly reduced peritoneal thickening. Furthermore, peritoneal function assessed by peritoneal equilibration test was significantly improved by spironolactone. Our results suggest that MR is a potential target to prevent inflammation-induced PF in patients on peritoneal dialysis.

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