研究趨化激素-17在腎臟纖維化之角色

慢性腎臟病病人係腎功能在幾個月到數年期間逐漸而難以逆轉的衰退，其中腎臟纖維化在慢性腎臟病中的一個重要病理變化。此種現象主要是發生在腎臟的腎單位經由過濾或再吸收過程所造成。一旦腎臟損傷時腎絲球或空腔滲透發炎細胞活化，因而產生活性氧化物質(Reactive oxygen species，ROS)、纖維化訊息和發炎細胞激素等訊息。C-C趨化因子配體-17(C-C chemokine ligand 17，CCL-17)，之前命名為胸腺趨化因子(thymus and activation-regulated chemokine ，TARC)，它也是CCR4的配位子之一。有文獻報導指出CCL-17與發炎反應有關，例如動脈粥狀硬化、內毒素休克、發炎性腸道疾病和肺纖維化有直接關係。但CCL-17在腎臟纖維化的角色，至今仍然未知。利用人類細胞激素生物晶片和酵素免疫分析法測量血漿內CCL-17和CCL-22在慢性腎臟病病人和健康人的表現量，實驗結果證實隨著慢性腎病的惡性程度增加。此外，慢性腎臟病第三、四、五期病人(eGFR<60)血漿內CCL-17表現量比慢性腎臟病第一、二病人(eGFR>60)還高，具有顯著差異。我們也發現糖尿病病人血漿內CCL-17的表現量與慢性腎臟病病人的期數無顯著關係。另外我們也證實高血壓病人血漿內CCL-17的表現量較高與慢性腎臟病病人期數有正相關，具有顯著差異。接下來利用單側輸尿管阻塞動物模式(Unilateral ureteral obstruction，UUO)和化學免疫染色法證實隨著天數增加，CCL-17蛋白表現量也逐漸增加。我們加入不同濃度Rh-CCL17處理 HK-2細胞會增加細胞內CCL-17、collagen和vimentin表現，反之，抑制E-cadherin表現。此項研究說明CCL-17可能參與慢性腎臟病的進程，我們期許未來CCL-17可以當作慢性腎臟病的生物標誌物或臨床診斷分子。

Chronic renal disease (CKD) means irreversible decline of renal function for months or years. Fibrosis can occur in either the filtering or reabsorptive component of the nephron, the functional unit of the kidney. When renal injury occurs, glomerular or interstitial infiltrated inflammatory cells become activated and produce injurious molecules such as ROS, as well as fibrogenic and inflammatory cytokines. The C-C chemokine ligand 17 (CCL-17), previously termed thymus and activation-regulated chemokine (TARC), a ligand of CCR4. CCL-17 has been reported to play an important role in inflammatory diseases, such as atherosclerosis, endotoxic shock, inflammatory bowel disease and pulmonary fibrosis. The purpose of this study is to confirm the relationship CCL-17 and CKD, and to further understand the molecular mechanisms of CCL-17 in CKD. Human cytokine antibody assay and Enzyme-linked immunosorbent assay (ELISA) assay were used to measure the plasma levels of CCL-17 and CC-L22 in CKD patients and healthy controls, we found that the level of plasma CCL-17 was significantly elevated in CKD patients compared to that in healthy controls. Moreover, plasma CCL-17 levels were significantly higher in the high malignant CKD patients (eGFR<60) than low malignant CKD patients (eGFR>60). We found that plasma CCL-17 levels in patients with diabetes were not significantly associated with the high or low malignant CKD patients. We found that plasma CCL-17 levels in patients with hypertension were significantly associated with the high malignant CKD patients (eGFR<60). In addition, mice with UUO (Unilateral ureteral obstruction) model and immunohistochemistry assay exhibited time-dependent increased protein levels of CCL-17. We also treated with different concentration of Rh-CCL17 were increased the expression of CCL-17, collagen, vimentin, and decreased the expression of E-cadherin in HK-2 cells. We perspective of understanding the impact of CCL-17 for CKD, and contribute to biomarker or clinical diagnosis of CKD in future.