Lipoic acid supplementation prevents cyclosporine-induced hypertension and nephrotoxicity in spontaneously hypertensive rats
| Autor: | Marjut Louhelainen, Risto Lapatto, Piet Finckenberg, Eero Mervaala, Saara Merasto, Zhongjian Cheng |
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| Rok vydání: | 2006 |
| Předmět: |
Male
medicine.medical_specialty Physiology Blood Pressure medicine.disease_cause Antioxidants Nephrotoxicity chemistry.chemical_compound Atrial natriuretic peptide Rats Inbred SHR Internal medicine Internal Medicine Animals Medicine Endothelial dysfunction Kidney NADPH oxidase Thioctic Acid biology business.industry Nitrotyrosine medicine.disease Rats Lipoic acid medicine.anatomical_structure Endocrinology chemistry Hypertension Cyclosporine biology.protein Kidney Diseases Cardiology and Cardiovascular Medicine business Oxidative stress |
| Zdroj: | Journal of Hypertension. 24:947-956 |
| ISSN: | 0263-6352 |
| DOI: | 10.1097/01.hjh.0000222766.37971.9f |
| Popis: | BACKGROUND Cyclosporine (CsA) has significantly improved long-term survival after organ transplantations. Hypertension and nephrotoxicity are common side effects during CsA treatment and are aggravated by high salt intake. OBJECTIVE To examine whether lipoic acid (LA), a natural antioxidant that scavenges reactive oxygen species and regenerates/recycles endogenous antioxidants, could prevent CsA-induced hypertension and nephrotoxicity. METHODS Six-week-old spontaneously hypertensive rats (SHR) on a high-sodium diet (NaCl 6%) received CsA [5 mg/kg subcutaneously (s.c.)] alone or in combination with LA (0.5% w/w) for 6 weeks. Blood pressure, arterial functions, and tissue morphology were determined. Immunohistochemistry, quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and high-pressure liquid chromatography were used for kidney and heart samples. RESULTS CsA induced severe hypertension, cardiac hypertrophy, endothelial dysfunction, and pronounced albuminuria. Histologically, the kidneys showed severe thickening of the media of the afferent arteries with fibrinoid necrosis, perivascular monocyte/macrophage infiltration and nitrotyrosine overexpression. CsA induced the expression of fibrogenic connective tissue growth factor both in the heart and kidneys. The detrimental effects of CsA were associated with upregulation of myocardial atrial natriuretic peptide (ANP) mRNA expression, paradoxical activation of the renin-angiotensin system (RAS), induction of renal reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and overexpression of oxidative stress-induced transcription factor NRF2. LA lowered blood pressure, ameliorated cardiac hypertrophy and endothelial dysfunction, and totally normalized albuminuria. In LA-treated rats, renal and cardiac morphologies were indistinguishable from those of SHR controls. CsA-induced myocardial ANP and connective tissue growth factor (CTGF) mRNA overexpression, RAS activation, NADPH oxidase induction, and NRF2 overexpression were prevented by LA. LA induced the mRNA expression of gamma-glutamylcysteine ligase, the rate-limiting enzyme in glutathione synthesis, and markedly increased hepatic cysteine and glutathione concentrations. CONCLUSIONS Our findings suggest a salutary role for lipoic acid supplementation in the prevention of CsA-induced hypertension and nephrotoxicity, and underscore the importance of increased oxidative stress in the pathogenesis of CsA toxicity. |
| Databáze: | OpenAIRE |
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