Epigallocatechin-3-gallate, L-theanine and theophylline abolish high-glucose-induced renal cell senescence and subsequent epithelial-mesenchymal transition and fibroblast activation via SIRT1/PGC-1α axis: Implications for diabetic kidney disease

ABSTRACT Recent research has highlighted the converging step of diabetic kidney disease (DKD) and chronic kidney disease (CKD) at cellular senescence and fibrotic processes. Therefore, therapeutic interventions targeting cellular senescence may ameliorate or slow the progression of DKD and CKD. This study evaluated the anti-senescence properties of the three most abundant phytochemicals in green tea, including epigallocatechin-3-gallate (EGCG), L-theanine and theophylline, in proximal tubular epithelial cells (PTECs) exposed to high-glucose. Additionally, their anti-fibrotic activities were examined in distal tubular epithelial cells (DTECs) and renal fibroblasts treated with the conditioned medium containing senescence-associated secretory phenotypes (SASPs) secreted from high-glucose-treated PTECs. The results showed that high-glucose triggered various senescence markers in PTECs, including cell enlargement, increased senescence-associated β-galactosidase activity, increased p21 level, S-phase cell-cycle arrest, suppressed cellular metabolic activity, and elevated SASPs levels. While phosphorylated (p)-p38, p-glycogen synthase kinase-3β (p-GSK-3β) and β-catenin remained unchanged, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) were suppressed by high-glucose. Moreover, the conditioned medium containing SASPs secreted from high-glucose-treated PTECs induced epithelial-mesenchymal transition (EMT) (shown by decreased E-cadherin and zonula occludens-1 (ZO-1), and increased vimentin and fibronectin) in DTECs and renal fibroblast activation (shown by increased fibronectin, collagen 1α, vimentin and actin stress fiber). However, EGCG, L-theanine and theophylline effectively abolished all these high-glucose-induced effects on senescence and SIRT1/PGC-1α axis in PTECs, EMT in DTECs, and renal fibroblast activation. In summary, this study highlights the anti-senescence, anti-EMT and anti-fibrotic properties of these green tea bioactive compounds via SIRT1/PGC-1α axis to counteract the high-glucose-induced effects in DKD.