Mineralocorticoid receptor blockade ameliorates peritoneal fibrosis in new rat peritonitis model.

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 (alpha-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-beta (TGF-beta), 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-beta, PAI-1, and Sgk1, were significantly suppressed by spironolactone (10 mg x kg(-1) x day(-1)). The effects of spironolactone (10 and 20 mg x kg(-1) x 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.

• Authors: Hayato Nishimura, Yasuhiko Ito, Masashi Mizuno, Akio Tanaka, Yoshiki Morita, Shoichi Maruyama, Yukio Yuzawa, Seiichi Matsuo
• Journal: American journal of physiology. Renal physiology (Am J Physiol Renal Physiol) Vol. 294 Issue 5 Pg. F1084-93 (May 2008) ISSN: 1931-857X [Print] United States
• PMID: 18353870 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hormone Antagonists
• Immediate-Early Proteins
• Mineralocorticoid Receptor Antagonists
• Spironolactone
• RNA
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Animals
• Blood Pressure (physiology)
• Blotting, Western
• Cells, Cultured
• Electrophoresis, Polyacrylamide Gel
• Fibroblasts
• Fibrosis (drug therapy)
• Hormone Antagonists (therapeutic use)
• Immediate-Early Proteins (biosynthesis, genetics)
• Immunohistochemistry
• Macrophages (pathology)
• Microscopy, Electron
• Mineralocorticoid Receptor Antagonists
• Neutrophils (pathology)
• Peritonitis (drug therapy, pathology, physiopathology)
• Protein Serine-Threonine Kinases (biosynthesis, genetics)
• RNA (biosynthesis, isolation & purification)
• Rats
• Rats, Sprague-Dawley
• Reverse Transcriptase Polymerase Chain Reaction
• Spironolactone (therapeutic use)