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，而許多研究證實，發炎反應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，辨認外來病原或來自受傷細胞所釋放的物質而引起發炎反應。近年來，研究發現TLR2參與在ischemia/reperfusion引起的腎臟病變中，顯示TLR2在調控腎臟病變中扮演重要角色。在本研究中發現TLR2表現量在糖尿病小鼠腎臟中有顯著性升高，但在肝臟及肺臟中則否。根據以上文獻及實驗結果，可假設高血糖所引起的細胞傷害，活化了TLR2及發炎反應，最終加速糖尿病腎病之形成。在此研究中，我首先建立streptozotocin (STZ) 刺激引起的糖尿病小鼠模式。在高血糖三至四個月後，糖尿病小鼠身上有腎臟功能缺損現象，包括微蛋白尿、腎臟肥大及基質堆積。Proinflammatory cytokine (TNF-a、IL-10、IL12)、chemokines (MCP1、MIP2、KC、IP10) 以及marcrophage marker (CD68、F4/80) 皆在糖尿病小鼠腎臟中顯著升高。已知會透過TLR2刺激cytokines及/或chemokines表現升高的傷害相關物質，包括biglycan、hyaluronic acid synthase 2 (HAS2)及HSP70皆在糖尿病小鼠腎臟中顯著升高。經以上結果表示，在高血糖環境中，TLR2也許能調控腎臟細胞傷害所引起的發炎反應。為了進一步探討TLR2在糖尿病腎病變中的重要性，我們使用STZ將TLR2缺失(Tlr2-/-)小鼠刺激引起糖尿病並觀察其腎臟功能是否較WT控制組好。在早期糖尿病中，Tlr2-/-糖尿病小鼠腎臟肥大情形較WT控制組輕微許多，但此現象並未在較後期糖尿病中發現。然而，微蛋白尿情形在Tlr2-/-糖尿病小鼠及WT控制組中並無差異。由以上可知，TLR2缺失可延緩糖尿病引起的腎臟肥大。為了進一步檢測TLR2缺失造成的腎臟肥大延緩是否與發炎反應及ECM堆積有關，我們以Realtime-PCR方式偵測fibronectin及cytokine/chemokine mRNA表現量。在早期糖尿病，fibronectin、cytokine及chemokine mRNA皆在Tlr2-/-糖尿病小鼠中有較低表現量。因此，TLR2缺失造成的腎臟肥大延緩與發炎反應及ECM堆積有關。由以上實驗結果，我們認為在糖尿病中，傷害相關物質活化了TLR2，引起發炎反應及ECM堆積而造成腎臟肥大。

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and a number of studies have demonstrated the significance of inflammation in DN. Toll-like receptors (TLRs), which respond to a variety of pathogens, transduce the inflammatory signals in the innate immunity. In addition to its pathogen recognition characteristic, TLRs have also been implicated in the recognition of endogenous host molecules during cellular injury. Recent study demonstrated that TLR2 participated in the kidney ischemia/reperfusion injury, suggesting that TLR2 signaling plays an important role in mediating kidney damage. Therefore, we hypothesize that cellular injury induced by hyperglycemia activates TLR2 signaling and inflammation resulting in acceleration of the development of DN. To study the role of TLR2 in DN, we employed the streptozotocin (STZ)-induced diabetic mouse model. 3~4 months after hyperglycemia, diabetic mice exhibited kidney dysfunction characterized by albuminuria, kidney hypertrophy and matrix deposition. We found that the increase of TLR2 expression was significant in kidney, but less evident in liver and lung of diabetic mice. Cytokines (TNF-a, IL-10 and IL-12, chemokines (MCP1, MIP2, KC and IP10) and macrophage marker (CD68 and F4/80) were upregulated in diabetic kidneys. Injury-associated host molecules known to stimulate the expression of cytokines and/or chemokines through TLR2, including biglycan and hyaluronic acid synthase 2 (HAS2) and HSP70, were increased in diabetic kidneys. Thus, these suggest that TLR2 may mediate the cellular injury-induced inflammation in diabetic kidney under persistent hyperglycemia. To directly address the involvement of TLR2 in the pathogenesis of DN, we employed Tlr2-/- mice in the STZ-induced DN mouse model. Kidney hypertrophy was attenuated in Tlr2-/- diabetic mice at early stage after diabetes but this attenuation was not existed at late stage. No difference in albuminuria was detected between Tlr2-/- and WT mice at all stages after diabtes. The delay of kidney hypertrophy by TLR2 deficiency was associated with reduced expressions of fibronectin, cytokines and chemokines at early stage after diabetes. These suggest that TLR2 deficiency postpones diabetes-induced kidney hypertrophy, which is likely mediated through the decreases in inflammation and ECM accumulation at early stage of DN. Thus, our results underscore the importance of TLR2 in regulating inflammation by engagement with ligands released from damaged host cells in the development of DN. These further provide a basis for therapeutic strategies to prevent or treat DN.

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