肾移植后肾脏中N-ε-羧甲基赖氨酸的沉积

Renal N(epsilon)-carboxymethyllysine deposition after kidney transplantation.

作者信息

Baumann Marcus, Caron Marjolein, Schmaderer Christoph, Schulte Christian, Viklicky Ondreij, von Weyhern Claus Werner Hann, Lutz Jens, Heemann Uwe

机构信息

Department of Pharmacology and Toxicology, University Maastricht, Maastricht, The Netherlands.

出版信息

Transplantation. 2008 Jul 27;86(2):330-5. doi: 10.1097/TP.0b013e31817ef7a5.

DOI:10.1097/TP.0b013e31817ef7a5

PMID:18645498

Abstract

BACKGROUND

Accumulation of advanced glycation end products, that is, N(epsilon)-carboxymethyllysine (CML), induces oxidative stress and inflammation, and is present in chronic renal failure. Proximal tubular cells (PTCs) take up advanced glycation end products-bound proteins by apical megalin-receptors and degrade them. We hypothesized that renal transplant dysfunction affects renal CML homeostasis. Therefore, tubular and glomerular deposition of CML was investigated in a rat transplantation model, and in human allograft biopsies.

METHODS

Fisher 344 kidneys were orthotopically transplanted into Lewis recipients. Recipients were treated with placebo, angiotensin II type 1 receptor blocker (candsartan 5 mg/kg/day), or calcium channel blocker (lacidipine 1 mg/kg/day) more than 28 weeks posttransplantation. Grafts were harvested at 12, 20, and 28 weeks posttransplantation. Sixty-two renal transplant patients underwent graft biopsy because of creatinine increase. Biopsies were graded according to interstitial fibrosis and tubular atrophy. N(epsilon)-carboxymethyllysine and megalin were semiquantitatively investigated in rats and humans using immunohistochemistry.

RESULTS

In Fisher grafts, the development of transplant dysfunction was associated with a longitudinal increase in CML deposition in PTCs (week 12: 1.0+/-0.0, week 20: 1.5+/-0.3, week 28: 2.1+/-0.2, P<0.05). No glomerular deposition was present. In human graft biopsies, tubular CML deposition was negatively, and glomerular CML deposition was positively associated with transplant dysfunction (r=-0.29 and r=0.34; P<0.05). Megalin was reduced at advanced grades.

CONCLUSION

N(epsilon)-carboxymethyllysine deposition increased in rat PTCs with mild transplant dysfunction. In humans, tubular CML deposition decreased in parallel with the reduction of its cellular uptake mechanism (megalin). Furthermore, glomerular deposition could play a pathophysiological role in chronic allograft injury.

摘要

背景

晚期糖基化终末产物（即N - ε - 羧甲基赖氨酸，CML）的积累会诱导氧化应激和炎症反应，且存在于慢性肾衰竭中。近端肾小管细胞（PTCs）通过顶端巨膜蛋白受体摄取与晚期糖基化终末产物结合的蛋白质并将其降解。我们推测肾移植功能障碍会影响肾脏CML的稳态。因此，我们在大鼠移植模型和人类同种异体移植活检中研究了CML在肾小管和肾小球的沉积情况。

方法

将Fisher 344大鼠的肾脏原位移植到Lewis受体大鼠体内。移植后28周以上，受体大鼠分别接受安慰剂、血管紧张素II 1型受体阻滞剂（坎地沙坦5 mg/kg/天）或钙通道阻滞剂（拉西地平1 mg/kg/天）治疗。在移植后12周、20周和28周时获取移植物。62例肾移植患者因肌酐升高接受移植肾活检。活检根据间质纤维化和肾小管萎缩进行分级。使用免疫组织化学方法对大鼠和人类的N - ε - 羧甲基赖氨酸和巨膜蛋白进行半定量研究。

结果

在Fisher大鼠移植物中，移植功能障碍的发展与PTCs中CML沉积的纵向增加相关（第12周：1.0±0.0，第20周：1.5±0.3，第28周：2.1±0.2，P<0.05）。未发现肾小球沉积。在人类移植肾活检中，肾小管CML沉积与移植功能障碍呈负相关，而肾小球CML沉积与移植功能障碍呈正相关（r = -0.29和r = 0.34；P<0.05）。在高级别时巨膜蛋白减少。