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.