Renoprotective effects of mineralocorticoid receptor blockade in heminephrectomized (pro)renin receptor transgenic rats.
1. Nephropathy and elevated plasma aldosterone concentrations (PAC) have been observed in (pro)renin receptor transgenic (TG) rats. In the present study, we hypothesized that PAC and/or mineralocorticoid receptor contribute to the nephropathy of TG rats. To test this hypothesis, the effects of a high-sodium (8% NaCl) diet and heminephrectomy on PAC were examined. 2. Feeding of the high-sodium diet for 12 weeks similarly decreased PAC in TG and wild-type (WT) rats. Heminephrectomy further reduced PAC in TG rats fed a high-sodium diet, but had no effect on PAC in WT rats fed a high-sodium diet. 3. Next, the effects of eplerenone (125 mg/kg per day) and dietary salt restriction (0.36% NaCl diet) on proteinuria and renal morphology were examined in rats fed a high-sodium diet or subjected to heminephrectomy. Both eplerenone and dietary sodium restriction significantly reduced the arterial pressure of TG rats, but had no effect in WT rats. In TG rats, treatment with eplerenone significantly decreased urinary protein excretion, but dietary sodium restriction did not. 4. Nephrin and podocin mRNA levels, as determined by real-time quantitative reverse transcription-polymerase chain reaction, were significantly lower in TG rats than in WT rats. In TG rats, eplerenone treatment significantly increased nephrin mRNA levels, but not podocin mRNA levels. Dietary salt restriction significantly increased mRNA levels of both nephrin and podocin. Although zonula occludens (ZO)-1 mRNA levels were similar in both WT and TG rats, eplerenone treatment significantly decreased ZO-1 mRNA levels in TG rats. 5. The results of the present study suggest that the improvement in proteinuria following eplerenone treatment is independent of its effects on sodium balance and may be mediated by effects on the expression of slit diaphragm proteins.
Mizuguchi
Yuki
Y
Endocrinology and Anti-Ageing Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan.
Ichihara
Atsuhiro
A
Seki
Yasufumi
Y
Sakoda
Mariyo
M
Kurauchi-Mito
Asako
A
Narita
Tatsuya
T
Kinouchi
Kenichiro
K
Bokuda
Kanako
K
Itoh
Hiroshi
H
D000450:Aldosterone / Q000097:blood*; D000818:Animals; D000077545:Eplerenone; D006801:Humans; D007674:Kidney Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000451:Mineralocorticoid Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009392:Nephrectomy; D051381:Rats; D055647:Rats, Transgenic; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology*; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000093342:Prorenin Receptor
D000451:Mineralocorticoid Receptor Antagonists; D011956:Receptors, Cell Surface; D017673:Sodium Chloride, Dietary; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D000093342:Prorenin Receptor