Cheng O, Thuillier R, Sampson E, Schultz G, Ruiz P, Zhang X, Yuen P S T, Mannon R B
Transplantation Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Am J Transplant. 2006 Oct;6(10):2292-306. doi: 10.1111/j.1600-6143.2006.01493.x. Epub 2006 Aug 4.
Chronic allograft nephropathy (CAN) is a leading cause of kidney graft failure following transplantation. Its causes are complex and include both immunological and nonimmunological factors. Here we have studied the development of CAN in a mouse model of kidney transplantation comparing isografts and allografts. Unlike the normal histology and normal serum creatinine of the uninephrectomized, nonrejecting isografted mice (0.219 +/- 0.024 mg/dL), allografted mice demonstrated severe renal dysfunction (mean serum creatinine 0.519 +/- 0.061 mg/dL; p < 0.005) with progressive inflammation and fibrosis of the kidney. These animals also showed an increased expression of connective tissue growth factor (CTGF), both systemically and within the graft. CTGF was highly expressed in tubuloepithelial cells of allografts, along with alpha-smooth muscle actin, a marker of myofibroblasts, and transcriptionally associated with other markers of fibrosis. In vitro studies of tubular epithelium indicate that CTGF is capable of inducing EMT, independent of TGF-beta. Finally, in human transplant recipients, serum and urine CTGF levels are significantly elevated compared to naïve individuals. Urinary levels correlated with the histological presence of CAN. These studies suggest a critical role of CTGF in graft fibrogenesis, for both mouse and man. Thus, CTGF has potential as a biomarker of CAN, and also a therapeutic target in managing graft fibrosis.
慢性移植肾肾病（CAN）是肾移植后移植肾失功的主要原因。其病因复杂，包括免疫和非免疫因素。在此，我们在肾移植小鼠模型中比较了同基因移植和异基因移植，研究了CAN的发展情况。与未切除单侧肾、不发生排斥反应的同基因移植小鼠的正常组织学和正常血清肌酐水平（0.219±0.024mg/dL）不同，异基因移植小鼠表现出严重的肾功能障碍（平均血清肌酐0.519±0.061mg/dL；p<0.005），伴有肾脏进行性炎症和纤维化。这些动物还显示，全身及移植肾内结缔组织生长因子（CTGF）的表达增加。CTGF在异基因移植肾的肾小管上皮细胞中高表达，同时伴有α平滑肌肌动蛋白（肌成纤维细胞标志物），且在转录水平上与其他纤维化标志物相关。肾小管上皮细胞的体外研究表明，CTGF能够独立于转化生长因子β诱导上皮-间质转化（EMT）。最后，在人类移植受者中，与未接受移植者相比，血清和尿液中CTGF水平显著升高。尿液水平与CAN的组织学表现相关。这些研究表明，CTGF在小鼠和人类的移植肾纤维化形成中起关键作用。因此，CTGF有潜力作为CAN的生物标志物，也是治疗移植肾纤维化的一个治疗靶点。
