Abstract | BACKGROUND/AIMS: METHODS: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. RESULTS: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)- catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)- catenin, T- and N-cadherin. CONCLUSIONS: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.
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Authors | Adam T Whaley-Connell, Javad Habibi, Ravi Nistala, Vincent G DeMarco, Lakshmi Pulakat, Melvin R Hayden, Tejaswini Joginpally, Carlos M Ferrario, Alan R Parrish, James R Sowers |
Journal | American journal of nephrology
(Am J Nephrol)
Vol. 35
Issue 1
Pg. 90-100
( 2012)
ISSN: 1421-9670 [Electronic] Switzerland |
PMID | 22205374
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2011 S. Karger AG, Basel. |
Chemical References |
- Receptors, Mineralocorticoid
- Spironolactone
- Ribosomal Protein S6 Kinases
- TOR Serine-Threonine Kinases
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Topics |
- Albuminuria
(metabolism, pathology)
- Animals
- Animals, Genetically Modified
- Blood Pressure
- Immunohistochemistry
(methods)
- Kidney Tubules
(drug effects)
- Male
- Microscopy, Electron, Transmission
(methods)
- Oxidation-Reduction
- Oxidative Stress
- Rats
- Rats, Sprague-Dawley
- Receptors, Mineralocorticoid
(metabolism)
- Ribosomal Protein S6 Kinases
(metabolism)
- Spironolactone
(metabolism)
- TOR Serine-Threonine Kinases
(metabolism)
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