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.

TRPV1 Activation Exacerbates Hypoxia/Reoxygenation-Induced Apoptosis in H9C2 Cells via Calcium Overload and Mitochondrial Dysfunction

“…Therefore, we evaluated the efficiency of MB by detecting the expression of ATP synthase β, a known marker of MB [36,37]. As shown in Figure 4C, H/R induced a decrease of ATP synthase β expression.…”

Mitophagy: Basic Mechanism and Potential Role in Kidney Diseases

“…In a cisplatin-induced AKI model, a decreased mitochondrial mass was observed, indicating impaired mitochondrial biogenesis [83]. In a rat model with chronic cyclosporin A (CsA) treatment, mitochondrial DNA copy number, along with the expression of nuclear and mitochondrial DNA-encoded oxidative phosphorylation (OXPHOS) proteins, peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, and mitochondrial transcription factor-A (Tfam) was dramatically decreased [87]. Interestingly, in a mouse model with 5/6 nephrectomy, decreases of mitochondrial content also happened in muscles, which resulted in impaired exercise endurance, a well-documented feature in chronic kidney diseases [88].…”

Induction of mitochondrial biogenesis protects against acetaminophen hepatotoxicity

“…In extrahepatic tissues, kidney cells treated with pro-oxidants showed increased MB after the initial stress, and overexpressing Pgc-1α enhanced recovery of mitochondrial function (Rasbach et al, 2007). Pharmacological induction of MB enhances regeneration and recovery in various rodent models of acute kidney injury (Rehman et al, 2013; Whitaker et al, 2013; Funk and Schnellmann, 2013; Jesinkey et al, 2014; Garrett et al, 2014; Khader et al, 2014) as well as other models of tissue injury (Finck and Kelly, 2007; St-Pierre et al, 2005; Funk et al, 2010). …”