The aldosterone receptor antagonist spironolactone prevents peritoneal inflammation and fibrosis.

Abstract

Peritoneal fibrosis is a complication of patients with long-term continuous ambulatory peritoneal dialysis (CAPD). Reports have indicated that angiotensin (Ang) II may correlate with the development of peritoneal fibrosis. However, it is unknown whether aldosterone also has a role in the development of peritoneal inflammation and fibrosis. The aim of the present study was to clarify the role of aldosterone in peritoneal inflammation and fibrosis. A rat model of peritoneal inflammation and fibrosis was established by daily intraperitoneal injection of dialysates and lipopolysaccharide in a 4-day interval over a period of 7 days. The animals were randomly assigned to five groups as follows: control (C); peritoneal dialysis (PD); peritoneal dialysis-spironolactone (PD-S); peritoneal dialysis-cilazapril (PD-C); and peritoneal dialysis-spironolactone-cilazapril (PD-SC). After 30 days, the TGF-β1 concentration in dialysates from all treatment groups was determined by ELISA. The histopathology of the parietal peritoneum was examined, and the expression of MCP-1, c-Jun, fibronectin (FN) and TGF-β1 in the abdominal membrane was determined by immunohistochemistry. Mineralocorticoid receptor (MR), 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) and CYP11B2 (aldosterone synthase) were analyzed by real time-PCR. Collagen deposition was significantly higher in PD compared with the other groups. The expression of MR, 11β-HSD2 and CYP11B2 was significantly higher in PD compared with the other groups. Spironolactone and/or cilazapril treatment partially ablated the increase in monocyte chemoattractant protein (MCP)-1, p-c-Jun, transforming growth factor (TGF)-β1, FN, MR, 11β-HSD2 and CYP11B2. Furthermore, treatment with spironolactone and/or cilazapril also reduced the infiltration of CD-4- and ED-1-positive cells in rat peritoneal tissues after peritoneal fibrosis. Exogenous aldosterone may have a key role in the development of peritoneal inflammation and fibrosis. Spironolactone decreased peritoneal inflammation and fibrosis, which was associated with reduced secretion from peritoneal macrophages, inactivation of the c-Jun N-terminal kinase (JNK) pathway and subsequent downregulation of the expression of TGF-β1.

• Authors: Lei Zhang, Jian-Bing Hao, Lian-Sheng Ren, Jiu-Li Ding, Li-Rong Hao
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 94 Issue 8 Pg. 839-50 (Aug 2014) ISSN: 1530-0307 [Electronic] United States
• PMID: 24862968 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Anti-Inflammatory Agents
• Dialysis Solutions
• Mineralocorticoid Receptor Antagonists
• Receptors, Mineralocorticoid
• Tgfb1 protein, rat
• Transforming Growth Factor beta1
• Cilazapril
• Spironolactone
• Aldosterone

Topics

• Aldosterone (chemistry, metabolism)
• Angiotensin-Converting Enzyme Inhibitors (therapeutic use)
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Cilazapril (therapeutic use)
• Dialysis Solutions (chemistry)
• Disease Models, Animal
• Drug Therapy, Combination
• Lymphocytes (drug effects, immunology, metabolism, pathology)
• Macrophages (drug effects, immunology, metabolism, pathology)
• Male
• Mineralocorticoid Receptor Antagonists (therapeutic use)
• Peritoneal Dialysis, Continuous Ambulatory (adverse effects)
• Peritoneal Fibrosis (etiology, immunology, pathology, prevention & control)
• Peritoneum (drug effects, immunology, metabolism, pathology)
• Peritonitis (etiology, immunology, pathology, prevention & control)
• Random Allocation
• Rats
• Rats, Wistar
• Receptors, Mineralocorticoid (chemistry, metabolism)
• Spironolactone (therapeutic use)
• Transforming Growth Factor beta1 (analysis, antagonists & inhibitors, metabolism)