Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Urology, Andrology and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Am J Transplant. 2016 Jan;16(1):325-33. doi: 10.1111/ajt.13415. Epub 2015 Aug 17.
Klotho is an anti-aging factor mainly produced by renal tubular epithelial cells (TEC) with pleiotropic functions. Klotho is down-regulated in acute kidney injury in native kidney; however, the modulation of Klotho in kidney transplantation has not been investigated. In a swine model of ischemia/reperfusion injury (IRI), we observed a remarkable reduction of renal Klotho by 24 h from IRI. Complement inhibition by C1-inhibitor preserved Klotho expression in vivo by abrogating nuclear factor kappa B (NF-kB) signaling. In accordance, complement anaphylotoxin C5a led to a significant down-regulation of Klotho in TEC in vitro that was NF-kB mediated. Analysis of Klotho in kidneys from cadaveric donors demonstrated a significant expression of Klotho in pre-implantation biopsies; however, patients affected by delayed graft function (DGF) showed a profound down-regulation of Klotho compared with patients with early graft function. Quantification of serum Klotho after 2 years from transplantation demonstrated significant lower levels in DGF patients. Our data demonstrated that complement might be pivotal in the down-regulation of Klotho in IRI leading to a permanent deficiency after years from transplantation. Considering the anti-senescence and anti-fibrotic effects of Klotho at renal levels, we hypothesize that this acquired deficiency of Klotho might contribute to DGF-associated chronic allograft dysfunction.
Klotho 是一种抗衰老因子，主要由肾小管上皮细胞（TEC）产生，具有多种功能。Klotho 在急性肾损伤中的表达下调；然而，肾移植中 Klotho 的调节尚未被研究。在缺血/再灌注损伤（IRI）的猪模型中，我们观察到从 IRI 开始 24 小时内肾脏 Klotho 显著减少。C1 抑制剂抑制补体可通过消除核因子 kappa B（NF-kB）信号来体内保留 Klotho 的表达。相应地，补体过敏毒素 C5a 导致体外 TEC 中 Klotho 的显著下调，这是 NF-kB 介导的。对尸肾供体肾脏中 Klotho 的分析表明，在移植前活检中 Klotho 表达显著；然而，与早期移植物功能正常的患者相比，患有延迟移植物功能（DGF）的患者的 Klotho 表达明显下调。移植后 2 年血清 Klotho 的定量分析表明，DGF 患者的 Klotho 水平显著降低。我们的数据表明，补体可能在 IRI 中下调 Klotho 中起关键作用，导致移植后多年来的永久性缺乏。考虑到 Klotho 在肾脏水平上的抗衰老和抗纤维化作用，我们假设这种获得性 Klotho 缺乏可能导致与 DGF 相关的慢性同种异体肾功能障碍。
