Jennings Paul, Koppelstaetter Christian, Aydin Sonia, Abberger Thomas, Wolf Anna Maria, Mayer Gert, Pfaller Walter
Division of Physiology, Department of Physiology and Medical Physics, Innsbruck Medical University, Innsbruck, Austria.
Am J Physiol Renal Physiol. 2007 Sep;293(3):F831-8. doi: 10.1152/ajprenal.00005.2007. Epub 2007 Jun 27.
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.
广泛使用的免疫抑制剂环孢素A（CsA）的肾毒性潜力已得到充分认识。然而，肾小管毒性的机制尚未完全阐明。慢性CsA肾病和肾脏器官老化具有一些共同的临床特征，如肾纤维化和肾小管萎缩，这增加了CsA可能通过诱导应激诱导的衰老表型发挥其某些有害作用的可能性。我们在体外对HK-2细胞和原代近端肾小管细胞中这一假设进行了研究。CsA诱导过氧化氢（H2O2）的产生，导致细胞周期停滞在G0/G1期，并抑制DNA合成。此外，暴露于CsA会导致端粒长度缩短、p53丝氨酸15磷酸化增加，并导致细胞周期抑制剂p21（Kip1）（CDKN1A）mRNA水平上调。在原代近端肾小管细胞中，暴露于CsA 13天后，p16（INK4a）（CDKN2A）表达增加，但在HK-2细胞中未出现这种情况。细胞与CsA和过氧化氢酶共同孵育能够防止端粒缩短，并部分恢复DNA合成。总之，CsA诱导人肾小管上皮细胞衰老，通过清除活性氧可使其减弱。
