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Published on: July 19, 2018
Prevention of lipopolysaccharide-induced peritoneal damage by eplerenone in rats undergoing peritoneal dialysis
Yosuke Tayama1, Hajime Hasegawa, Kaori Takayanagi
1Department of Nephrology and Hypertension, Saitama Medical Center, Saitama Medical University, Saitama - Japan.
Background:
Bacterial peritonitis in patients undergoing peritoneal dialysis (PD) is a major cause of therapy interruption due to peritoneal insufficiency. Here we studied the effect of a selective mineralocorticoid receptor (MR) blocker, eplerenone, on the prevention of peritoneal damage.
Methods:
Male Sprague-Dawley rats were treated with a daily infusion of human use PD solution (100 mL/kg i.p., PD group, n = 5), or with PD solution and intermittent intraperitoneal injections of lipopolysaccharide (LPS group, n = 5) or with LPS and eplerenone (100 mg/ kg/d, po, Ep group, n = 5) for 4 weeks. Peritoneal samples were subjected to assessment following the peritoneal equilibration test (PET).
Results:
Histological observations revealed that LPS treatment resulted in significant peritoneal thickening associated with increased ED-1-positive cell infiltration and the number of transforming growth factor (TGF)-β1-positive cells, and that eplerenone reduced these changes. LPS administration also evoked significant upregulation of monocyte chemotactic protein-1 and TGF-β1, which were inhibited by eplerenone. PET revealed that ultrafiltration and transperitoneal osmotic diffusion were significantly impaired by LPS and restored by eplerenone. Increased value of the mass transfer area coefficients for creatinine values was also recovered by Ep (0.10 ± 0.01 in the PD, 0.14 ± 0.02 in the LPS and 0.08 ± 0.0 in the Ep groups). Immunostaining for von Willebrand factor showed a significant increase by LPS and its restoration by Ep.
Conclusions:
Ep effectively diminished LPS-induced peritoneal insufficiency. A selective blockade of MR might prevent peritoneal insufficiency associated with bacterial peritonitis.
Insights
Eplerenone, a mineralocorticoid receptor (MR) blocker, effectively prevented peritoneal insufficiency and damage caused by bacterial peritonitis in a rat model. This suggests MR blockade may be a therapeutic strategy for patients undergoing peritoneal dialysis.
Area of Science:
- Nephrology
- Pharmacology
- Pathology
Background:
- Bacterial peritonitis is a common complication of peritoneal dialysis (PD), often leading to therapy cessation due to peritoneal damage.
- Mineralocorticoid receptor (MR) overactivation is implicated in fibrotic processes contributing to peritoneal insufficiency.
Purpose of the Study:
- To investigate the protective effects of eplerenone, a selective MR blocker, against peritoneal damage induced by bacterial peritonitis in a rat model.
Main Methods:
- Rats received PD solution, PD solution with lipopolysaccharide (LPS), or LPS with eplerenone for 4 weeks.
- Peritoneal function was assessed using the peritoneal equilibration test (PET).
- Histological and molecular analyses evaluated peritoneal thickening, inflammation, and fibrosis markers.
Main Results:
- LPS-induced peritoneal thickening, inflammation (ED-1, TGF-β1, MCP-1 upregulation), and fibrosis were significantly reduced by eplerenone.
- Eplerenone restored impaired ultrafiltration and solute transport during PET.
- LPS-induced increase in von Willebrand factor was normalized by eplerenone.
Conclusions:
- Selective MR blockade with eplerenone effectively mitigates peritoneal insufficiency and damage associated with bacterial peritonitis.
- MR antagonism presents a potential therapeutic avenue for preventing peritoneal complications in PD patients.
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