Cyclosporine A induces senescence in renal tubular epithelial cells

Abstract

The nephrotoxic potential of the widely used immunosuppressive agent cyclosporine A (CsA) is well recognized. However, the mechanism of renal tubular toxicity is not yet fully elucidated. Chronic CsA nephropathy and renal organ aging share some clinical features, such as renal fibrosis and tubular atrophy, raising the possibility that CsA may exert some of its deleterious effects via induction of a stress-induced senescent phenotype. We investigated this hypothesis in HK-2 cells and primary proximal tubular cells in vitro. CsA induced the production of H2O2, caused cell cycle arrest in the G0/G1 phase, and inhibited DNA synthesis. Furthermore, CsA exposure lead to a reduction of telomere length, increased p53 serine 15 phosphorylation, and caused an upregulation of the cell cycle inhibitor p21(Kip1) (CDKN1A) mRNA levels. CsA caused an increase in p16(INK4a) (CDKN2A) expression after a 13-day exposure in primary proximal tubular cells but not in HK-2 cells. Coincubation of cells with CsA and catalase was able to prevent telomere shortening and partially restored DNA synthesis. In summary, CsA induces cellular senescence in human renal tubular epithelial cells, which can be attenuated by scavenging reactive oxygen species.

H2O2Accumulation Mediates Differentiation Capacity Alteration, But Not Proliferative Decline, in Senescent Human Fetal Mesenchymal Stem Cells

“…4B). These findings are compatible to the previous finding of H 2 We then examined whether ROS, as induced by toxic compounds or direct exposure of H 2 O 2 , was the cause of the increased p21 expression and cell cycle arrest in L-PDMCs, since this has been reported previously (16,22). However, we found that NAC inhibition of H 2 O 2 accumulation had no effect on cell cycle arrest (Fig.…”

Y-Box Binding Protein-1 Mediates Profibrotic Effects of Calcineurin Inhibitors in the Kidney

“…Because YB-1 is important in preventing premature senescence, which has been demonstrated in YB-1 knockdown mice (44), a diminished YB-1 content may cause an impaired proliferation. This is in line with the observations in renal tubular epithelial cells, in which CsA mediates cell cycle arrest (45) and enhanced senescence (46), potentially mediated by YB-1 depletion.…”

Impact of ER stress-regulated ATF4/p16 signaling on the premature senescence of renal tubular epithelial cells in diabetic nephropathy

“…Premature senescence was observed in renal cells under conditions of high glucose, oxidative stress, or ischemia reperfusion injury (17,18,35). p21 and p16 pathways are very important signaling pathways of premature senescence in renal inherent cells (23).…”