Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats.
BACKGROUND
We evaluated the role of aldosterone as a mediator of renal inflammation and fibrosis in a rat model of aldosterone/salt hypertension using the selective aldosterone blocker, eplerenone.


METHODS
Unnephrectomized, Sprague-Dawley rats were given 1% NaCl (salt) to drink and randomized to receive treatment for 28 days: vehicle infusion (control); 0.75 microg/hour aldosterone subcutaneous infusion; or aldosterone infusion + 100 mg/kg/day oral dose of eplerenone. Blood pressure and urinary albumin were measured and kidneys were evaluated histologically. Renal injury, inflammation, and fibrosis were assessed by immunohistochemistry, in situ hybridization, and reverse transcription-polymerase chain reaction (RT-PCR).


RESULTS
Aldosterone/salt induced severe hypertension compared to controls (220 +/- 4 mm Hg vs. 131 +/- 4 mm Hg, P < 0.05), which was partially attenuated by eplerenone (179 +/- 4 mm Hg, P < 0.05). In aldosterone/salt treated rats, renal histopathologic evaluation revealed severe vascular and glomerular sclerosis, fibrinoid necrosis and thrombosis, interstitial leukocyte infiltration, and tubular damage and regeneration. Aldosterone/salt increased circulating osteopontin (925.0 +/- 80.2 ng/mL vs. 53.6 +/- 6.3 ng/mL) and albuminuria (75.8 +/- 10.9 mg/24 hours vs. 13.2 +/- 3.0 mg/24 hours) compared to controls and increased expression of proinflammatory molecules. Treatment with eplerenone reduced systemic osteopontin (58.3 +/- 4.2 ng/mL), albuminuria (41.5 +/- 7.2 mg/24 hours), and proinflammatory gene expression: osteopontin (OPN), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and interleukin-1beta (IL-1beta).


CONCLUSIONS
These findings indicate that aldosterone/salt-induced renal injury and fibrosis has inflammatory components involving macrophage infiltration and cytokine up-regulation. Attenuation of renal damage and inflammation by eplerenone supports the protective effects of aldosterone blockade in hypertensive renal disease.
Blasi
Eileen R
ER
Pharmacia Corporation, Cardiovascular and Metabolic Diseases, Global Medical Affairs, and Global Toxicology, St. Louis, Missouri 63167, USA.
Rocha
Ricardo
R
Rudolph
Amy E
AE
Blomme
Eric A G
EA
Polly
Melissa L
ML
McMahon
Ellen G
EG
D000450:Aldosterone / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D016207:Cytokines / Q000378:metabolism; D000077545:Eplerenone; D005355:Fibrosis; D006977:Hypertension, Renal / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D009393:Nephritis / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride / Q000494:pharmacology*; D013148:Spironolactone / Q000031:analogs & derivatives* / Q000494:pharmacology
D016207:Cytokines; D013148:Spironolactone; D012965:Sodium Chloride; D000450:Aldosterone; D000077545:Eplerenone