在現今的社會中，糖尿病腎病變已是一個全球必需關注的議題，而且它還是主要導致末期腎臟病的因素，近年來，許多研究都指出足細胞在糖尿病腎病變中扮演著相當重要的角色，儘管現在的研究已經從基因層面去了解此疾病的致病機制，但至今仍無有效的治療方法，然而，近年來表觀遺傳研究的出現為治療糖尿病腎病變帶來一絲曙光， 而其中異染色質所調控的表觀遺傳機制在腎臟的功能方面還尚未清楚，所以我們透過果蠅餵食高糖去建立一個高血糖所導致的糖尿病腎病變的模式，再利用這個模式去探討一個主要構成異染色質的異染色質蛋白 1 在這個疾病中扮演著什麼樣的角色。首先，我們透過兩種不同的餵食方式誘導果蠅腎臟功能缺失，分別是在幼蟲時期餵食高糖以及羽化後再進行高糖的餵食，我們發現幼蟲時期的高糖餵食導致果蠅有發育遲緩的現象而且其足細胞的功能也受到損害，而在成蟲時期的長時間高糖餵食也發現到類似的情形，我們發現到長時間的高糖餵食導致果蠅的足細胞的功能隨著老化漸漸受到損害並且減少果蠅的壽命，有趣的是我們還發現到長時間的高糖飲食會使足細胞內異染色質的表達量增加，但是隨著老化，異染色質的表達量逐漸下降與之前的文獻結果相符合，另外，我們還發現到隨著年紀的增長果蠅足細胞的尺寸逐漸變大。再者，之前的研究發現到如果減少異染色質蛋白 1的表達量可以使一個在果蠅足細胞裂隙隔膜上的重要穿膜蛋白Kirre的表達量上升，而且我們透過線上的資料庫分析發現到在Kirre這個基因體上有許多組蛋白3離胺酸9甲基化的修飾位點，更重要的是我們在高糖長時間的高糖飲食下發現到Kirre的表達量會隨著老化下降。 這些證據都證實異染色質蛋白 1在高糖飲食引發的足細胞功能缺失中扮演著重要的角色，最後，我們的證據指出老化時高糖飲食下所導致的足細胞穿膜蛋白Kirre的減少是透過異染色質的產生去抑制它的，這個研究有助於我們透過表觀遺傳學的角度去了解高糖所誘導的足細胞功能缺失的分子機制，來提供我們一個新的想法去治療糖尿病腎病變的足細胞功能損害。

Diabetic nephropathy (DN), a growing global health problem, is the leading cause of end-stage kidney disease. Despite recent advances in genetic mechanisms of DN, effective therapeutics of DN are still lacking, suggesting that epigenetic mechanisms need to be explored in diabetic kidney disease. Furthermore, the molecular mechanisms by which heterochromatin, an important epigenetic complex, regulates renal functions remain unknown. Here, we use Drosophila as an animal model to investigate the role of Heterochromatin protein 1 (HP1), a major heterochromatin component, in high dietary sugar (HDS)-induced diabetic nephropathy. First, we establish two HDS induced renal failure models in larvae and adults, respectively. In the larval stage, HDS causes Drosophila developmental delay, and disrupts renal filtration function. In the adult stage, chronic HDS feeding decreases nephrocyte filtration function and longevity during aging. Interestingly, we found that long-term HDS treatment induces dynamic changes in the heterochromatin in which H3K9me2 and HP1 levels increase upon HDS feeding in adult nephrocytes. Interestingly, the heterochromatin levels decrease in nephrocytes during aging. However, nephrocyte nucleus size is reduced by HDS in early adult life but is increased in late adult life. Furthermore, in Drosophila nephrocytes, we found that kirre which is an important slit-diaphragm gene with multiple H3K9me2 binding sites on the gene body, is upregulated by HP1 RNAi. Moreover, chronic HDS feeding reduces Kirre levels during aging. Thus, HDS reduces slit-diaphragm protein Kirre to disrupt nephrocyte filtration function during aging, by increasing heterochromatin formation. My study reveals novel epigenetic mechanisms involved in HDS-induced renal diseases and may provide new insights to identify new therapeutics for DN.

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