title: Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.
abstract: Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-β (AS-β) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate CsA-induced kidney injury, at least in part, through the stimulation of MB.
authors.affiliation: Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina, United States of America.
authors.forename: Hasibur
authors.initials: H
authors.lastname: Rehman
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Krishnasamy
authors.forename: Khujista
authors.initials: K
authors.lastname: Haque
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Thurman
authors.forename: John J
authors.initials: JJ
authors.lastname: Lemasters
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhong
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004272:DNA, Mitochondrial / Q000235:genetics; D004268:DNA-Binding Proteins; D004032:Diet; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D018628:Gene Dosage; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D007674:Kidney Diseases / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism; D063269:Mitochondrial Turnover / Q000187:drug effects*; D010085:Oxidative Phosphorylation; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D059808:Polyphenols / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D013662:Tea / Q000737:chemistry*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D004268:DNA-Binding Proteins; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D059808:Polyphenols; C501429:Ppargc1a protein, rat; D012333:RNA, Messenger; D013662:Tea; D014157:Transcription Factors; C422562:mitochondrial transcription factor A; D016572:Cyclosporine; C497342:ATP synthase beta subunit, rat; D025261:Mitochondrial Proton-Translocating ATPases; D042967:Electron Transport Complex I