title: 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.affiliation: The Second Ward of the Department of Nephrology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The Second Ward of the Department of Nephrology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Jian-Bing
authors.initials: JB
authors.lastname: Hao
authors.affiliation: The Second Ward of the Department of Nephrology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Ren
authors.affiliation: Hospital of Hei Long Jiang Province, Harbin, China.
authors.forename: Jiu-Li
authors.initials: JL
authors.lastname: Ding
authors.affiliation: The Second Ward of the Department of Nephrology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Hao
mesh_terms: D000450:Aldosterone / Q000737:chemistry / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D017315:Cilazapril / Q000627:therapeutic use; D015314:Dialysis Solutions / Q000737:chemistry; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D000451:Mineralocorticoid Receptor Antagonists / Q000627:therapeutic use*; D010531:Peritoneal Dialysis, Continuous Ambulatory / Q000009:adverse effects; D056627:Peritoneal Fibrosis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D010537:Peritoneum / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010538:Peritonitis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000378:metabolism; D013148:Spironolactone / Q000627:therapeutic use*; D053773:Transforming Growth Factor beta1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000893:Anti-Inflammatory Agents; D015314:Dialysis Solutions; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D017315:Cilazapril; D013148:Spironolactone; D000450:Aldosterone