糖尿病腎病 (diabetic nephropathy) 是多種糖尿病併發症之一，且為末期腎衰竭的主要原因，近幾年的研究證實發炎反應 (inflammation) 在糖尿病腎病中扮演重要的角色。在發炎反應中，已知可由toll-like receptors (TLRs) 啟動且辨認外來病原 (病原相關物質) 或來自受傷細胞所釋放的物質 (傷害相關物質)。研究顯示TLRs及其內生性配合體 (endogenous ligands) 皆在第二型糖尿病病患的單核細胞 (monocyte) 中顯著升高。同樣地，TLR2及其endogenous ligands在糖尿病腎病的大鼠腎臟中顯著增加。本實驗室之前的研究也發現在糖尿病腎病的小鼠腎臟中，TLR4 mRNA明顯增加。研究更指出，TLR4參與在ischemia/reperfusion引起的腎臟病變中，顯示TLR4在調控腎臟病變中扮演著重要角色。在糖尿病腎病的初期，血液中的白蛋白 (albumin) 便會通過腎絲球之過濾系統而到達腎小管管腔，這些通過腎絲球的白蛋白也被證實會促使近腎小管細胞發炎。根據以上文獻及實驗結果，可假設糖尿病的高血糖及到達腎小管的白蛋白活化TLR4所調控之發炎反應，進一步造成腎臟細胞損傷而加速糖尿病腎病形成。首先，為了確定TLR4在糖尿病腎病的角色，我們使用TLR4缺失小鼠 (Tlr4-/-) 並刺激引起糖尿病後觀察其腎臟功能是否較wild-type (WT) 控制組好。結果顯示，當TLR4缺失後，蛋白尿 (albuminuria) 與WT相比有回復的現象。除此之外，我們檢測了腎臟當中chemokines (MCP1、MIP2、IP10)、macrophage maker (F4/80)以及腎臟肥大因子 (TGF-β、fibronectin、collagen type Ⅳ) mRNA，在TLR4缺失的糖尿病小鼠的腎臟中，這些基因的表達量都較WT控制組低。由此可知，在糖尿病腎病中TLR4的缺失降低了發炎反應並進一步延緩了蛋白尿的發生。接著我們利用免疫組織染色的方法來觀察表現TLR4的細胞。實驗結果顯示，在糖尿病鼠的腎臟中，TLR4表現量會增加且主要表現在擴張的近腎小管。我們同時檢測 TLR4的內生性配合體 Heat shock protein 70 (Hsp70) 的表現量， Hsp70在糖尿病小鼠的腎臟表現量較控制組高。這些結果顯示著在糖尿病腎病中，TLR4調控的發炎反應主要位在近腎小管細胞且持續被其內生性配合體所活化。為了探討糖尿病中哪些分子會活化TLR4所調控之發炎反應及其下游的路徑，我們利用LLC-PK1這株近腎小管細胞來進行進一步的實驗。在給予細胞高濃度葡萄糖 (HG) 或含有白蛋白 (albumin) 的培養液24小時後，細胞MCP1及TNFα mRNA的表達量會顯著的升高。而若同時給予NF-ĸB的抑制物 CAPE之後，原本被HG或是albumin所刺激的MCP1 mRNA則會降低。除此之外，我們檢測了培養過細胞的培養液 (cell cultured medium)，Hsp70在albumin-treated conditioned medium中會顯著的增加。更進一步，當給與細胞這albumin-treated conditioned medium會促使細胞表達MCP1及TNFα。由以上可知，傷害相關物質會在albumin-treated conditioned medium中增加且活化發炎反應。總結我們的實驗結果，我們認為在糖尿病腎病中，TLR4的內生性配合體活化TLR4所調控之發炎反應且加速蛋白尿的形成而使得糖尿病腎病更為嚴重。

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Toll-like receptors (TLRs) are conserved in many species and recognize pathogen- and damage-associated molecular patterns (DAMPs). Studies showed that TLRs and TLR ligands were increased in the monocytes of T2DM patients, as well as in the kidney of diabetic rat. In addition, our previous results showed that TLR4 was highly expressed in the kidney from streptozotocin-induced DM mice. Furthermore, TLR4 was shown to be participated in the kidney ischemia/reperfusion injury, suggesting that TLR4 plays a role in kidney injury. Leakage of albumin into renal tubules is detected in the early stage of DN after hyperglycemia, and in vitro study showed that albumin induced renal proximal tubular cell inflammation. Therefore, we hypothesized that high glucose (HG) and/or albumin activate TLR4-mediated inflammatory response in renal cells and accelerate the development of DN. To study the role of TLR4, we employed TLR4-deficient mice and found that kidney dysfunction characterized by albuminuria was attenuated in diabetic Tlr4-/- mice. Moreover, up-regulations of chemokines (MCP1, MIP2 and IP10), macrophage maker (F4/80) and renal fibrosis factors (TGF-β, fibronectin and collagen type Ⅳ) were all attenuated in the kidney of Tlr4-/- diabetic mice. These data suggested that TLR4 deficiency ameliorated renal inflammation and improved the renal dysfunction in DN. Immunohistochemistry analysis revealed that TLR4 was expressed in renal proximal and distal tubules in the kidney of control mice, and it was up-regulated in dilated proximal tubules in the kidney of DM mice. Moreover, Hsp70, one of potential DAMPs of TLR4, was significantly increased in the kidney of diabetic mice. These suggested that TLR4-mediated inflammation takes place specifically in tubular cells under the stimulation of its potential endogenous ligands in DN. To investigate the upstream and downstream factors of TLR4-mediated inflammation, we further employed LLC-PK1, a porcine proximal tubular cell line. Compared to LG controls, mRNA levels of MCP1 and TNFα were significantly up-regulated in LLC-PK1 cells treated with high glucose (HG) or albumin. The increased expression of MCP1 induced by HG or albumin was attenuated by NF-ĸB inhibitor, CAPE. Furthermore, Hsp70 was increased in the cultured medium of LLC-PK1 cells treated with albumin but not with HG. The Hsp70 in albumin-treated conditioned medium further induced the expression of MCP1 and TNFα in LLC-PK1 cells. These indicated that DAMPs in the conditioned medium of LLC-PK1 cells treated with albumin activated inflammatory responses in renal cells. Thus, our study emphasizes the importance of TLR4 in regulating inflammation by engagement with potential endogenous ligands released from damaged renal cells caused by high glucose or albumin in the development of DN. These further provide a basis for therapeutic strategies to prevent or treat DN.

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