第二型血管生成素在糖尿病腎臟病變的機轉角色及臨床預後探討

台灣是全世界末期腎臟病發生率和盛行率最高的國家。糖尿病是造成慢性腎臟病的主要原發病因，糖尿病腎臟病變病人容易進入末期腎臟病進而接受長期透析治療，也容易增加住院機會和死亡預後。因此也造成台灣健保費用的重大負擔。糖尿病腎臟病變的病生理機轉相當多樣和複雜，目前尚未完整被世人了解。近幾年來，非傳統型的危險因子如內皮細胞失能已被證實和腎臟功能惡化有關。Angiopoietin (Angpt)-Tie ligand-receptor系統是負責在血管生成和血管發炎時調控內皮的強度和完整性。第二型血管生成素(Angpt2)在內皮細胞表現，平時儲存在Weibel-Palade bodies；第二型血管生成素受到外來刺激時會造成平靜的內皮細胞不穩定，進而調控發炎和血管生成的細胞激素。高濃度的第二型血管生成素可能會引起發炎反應、增加細胞間通透性，和造成細胞凋亡。目前已知第二型血管生成素會造成糖尿病眼底病變的細胞凋亡，也造成糖尿病心肌細胞死亡，而這些第二型血管生成素引發的傷害是否參與了腎臟功能惡化的過程，進而造成腎臟衰竭，仍不清楚。本博士論文研究假說為第二型血管生成素參與糖尿病腎臟病變之病生理機轉，影響病人的臨床預後。藉由跨領域研究，利用臨床病人、細胞與動物之實驗模式來印證第二型血管生成素在糖尿病腎臟病變的致病角色。從實驗結果可知第二型血管生成素和慢性腎臟病病人的腎臟預後有相關性。血漿中第二型血管生成素較高的慢性腎臟病病人腎功能容易快速下降，比較容易進入透析。此外，第二型血管生成素也可以預測糖尿病腎臟病變病人的腎臟預後。第二型血管生成素會藉由微小核醣核酸(microRNA)-33-5p-SOCS5路徑造成腎骼細胞(mesangial cell)凋亡，造成腎絲球的傷害，進而參與糖尿病腎臟病變之病生理機轉，影響到糖尿病病人的腎功能惡化並進入透析。因此，第二型血管生成素不僅能做為臨床預後標誌也能成為糖尿病腎臟病變的治療標靶。

關鍵字

第二型血管生成素；糖尿病腎臟病；慢性腎臟病；臨床預後

並列摘要

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) amd end-stage renal disease and accounts for 30~40% of individuals entering maintenance dialysis in Taiwan while it contributes to higher burdens of health insurance. The pathophysiological mechanisms of DN have still not been completely explored. Recently, endothelial dysfunction has been associated with renal progression. The angiopoietin (Angpt)/Tie ligand-receptor system tightly controls the endothelial phenotype during angiogenesis and vascular inflammation. Angpt2 is expressed in endothelial cells, and stored in Weibel-Palade bodies (WPB). Angpt2 destabilizes the quiescent endothelium and responses to exogenous stimuli, thereby modulating the inflammatory and angiogenic cytokines. Elevated Angpt2 levels trigger an inflammatory response, increased permeability, and apoptosis process which participate in renal progression. Angpt2 is highly expressed in diabetes and correlated with the markers of endothelial injury. Previous studies reported that Angpt2 caused pericyte apoptosis in diabetic retinopathy, and Angpt2 resulted in cardiac myocyte apoptosis in diabetic cardiomyopathy. However, the mechanisms that Angpt2 participates in renal progression are unknown. This study hypothesized that Angpt2 plays a role in pathophysiologic mechanisms of DN and affects clinical outcomes in DM patients. We conducted a cross-disciplinary study, including human, in vivo, and in vitro studies to examine the role of Angpt2 in DN. Study results found that circulating Angpt2 was significantly and positive associated with the increased risk for rapid renal function decline and commencing dialysis in patients with CKD or diabetic nephropathy. Angpt2 could predict renal outcomes in these two populations. Furthermore, Angpt2 caused mesangial cells apoptosis via miR-33-5p-SOCS5 loop in DN, leading to glomerular injury. In conclusion, Angpt2 is not only a predictor of clinical outcomes, but also a potential therapeutic target of DN.

並列關鍵字

Angiopoietin-2 ； diabetic nephropathy ； chronic kidney disease ； clinical outcome

參考文獻

1. Nugent RA, Fathima SF, Feigl AB, Chyung D. The burden of chronic kidney disease on developing nations: a 21st century challenge in global health. Nephron Clin Pract 2011;118: 269-277

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