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Renoprotection by statins is linked to a decrease in renal oxidative stress, TGF-β, and fibronectin with concomitant increase in nitric oxide bioavailability
- Source :
- American Journal of Physiology-Renal Physiology. 295:F53-F59
- Publication Year :
- 2008
- Publisher :
- American Physiological Society, 2008.
-
Abstract
- Clinical and experimental studies have provided evidence suggesting that statins exert renoprotective effects. To investigate the mechanisms by which statins may exert renoprotection, we utilized the hypertensive Dahl salt-sensitive (DS) rat model, which manifests cardiovascular and renal injury linked to increased angiotensin II-dependent activation of NADPH oxidase and decreased nitric oxide (NO) bioavailability. DS rats given high salt diet (4% NaCl) for 10 wk exhibited hypertension [systolic blood pressure (SBP) 200 ± 8 vs. 150 ± 2 mmHg in normal salt diet (0.5% NaCl), P < 0.05], glomerulosclerosis, and proteinuria (158%). This was associated with increased renal oxidative stress demonstrated by urinary 8-F2α-isoprostane excretion and NADPH oxidase activity, increased protein expression of transforming growth factor (TGF)-β (63%) and fibronectin (181%), increased mRNA expression of the proinflammatory molecules monocyte chemoattractant protein-1 (MCP-1) and lectin-like oxidized LDL receptor-1 (LOX-1), as well as downregulation of endothelial NO synthase (eNOS) activity (−44%) and protein expression. Return to normal salt had no effect on SBP or any of the measured parameters. Atorvastatin (30 mg·kg−1·day−1) significantly attenuated proteinuria and glomerulosclerosis and normalized renal oxidative stress, TGF-β1, fibronectin, MCP-1 and LOX-1 expression, and eNOS activity and expression. Atorvastatin-treated rats showed a modest reduction in SBP that remained in the hypertensive range (174 ± 8 mmHg). Atorvastatin combined with removal of high salt normalized SBP and proteinuria. These findings suggest that statins mitigate hypertensive renal injury by restoring the balance among NO, TGF-β1, and oxidative stress and explain the added renoprotective effects observed in clinical studies using statins in addition to inhibitors of the renin-angiotensin system.
- Subjects :
- medicine.medical_specialty
Nitric Oxide Synthase Type III
Physiology
Biological Availability
Nitric Oxide Synthase Type II
Blood Pressure
Kidney
Nitric Oxide
medicine.disease_cause
Nitric oxide
chemistry.chemical_compound
Transforming Growth Factor beta
Internal medicine
Atorvastatin
medicine
Animals
Pyrroles
RNA, Messenger
Chemokine CCL2
Rats, Inbred Dahl
NADPH oxidase
biology
Chemistry
NADPH Oxidases
Articles
Transforming growth factor beta
Scavenger Receptors, Class E
Fibronectins
Rats
Bioavailability
Oxidative Stress
Proteinuria
Endocrinology
medicine.anatomical_structure
Heptanoic Acids
biology.protein
Kidney Failure, Chronic
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Oxidative stress
Transforming growth factor
Subjects
Details
- ISSN :
- 15221466 and 1931857X
- Volume :
- 295
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Renal Physiology
- Accession number :
- edsair.doi.dedup.....3145672ab6dabf6ebfb2f01f327d0894