BACKGROUND One of the most important factors modulating endothelial health is acetylcholine, and while it is associated as a cholinergic neurotransmitter; it is also expressed by non-neuronal cells. However, its role in the kidney, which does not receive cholinergic innervation, remains unknown. METHODS To determine if acetylcholine is produced in the kidney, we used ChAT(BAC)-eGFP (ChAT mice) transgenic mice in which enhanced green fluorescent protein (eGFP) is expressed under the control of the endogenous choline acetyltransferase (ChAT) transcriptional regulatory elements. We then investigated the role of acetylcholine in kidney disease by inducing anti- glomerular basement membrane glomerulonephritis (anti-GBM GN) in ChAT transgenic mice. RESULTS We demonstrate ChAT, the sole enzyme responsible for acetylcholine production, was expressed in glomerular podocytes and produced acetylcholine. We also show during anti-GBM GN in ChAT transgenic mice, ChAT expression was induced in the glomeruli, mainly in podocytes and protects mice from kidney injury with marked reduction of glomerular proliferation/fibrinoid necrosis (by 71%) crescent formation (by 98%), and tubular injury (by 78%). In contrast, specific knockout of podocyte ChAT worsened the severity of the disease. The mechanism of protection included reduction of inflammation, attenuation of angiogenic factors reduction, and increase of eNOS expression. In vitro and in vivo studies demonstrated available drugs like cholinesterase inhibitors and ChAT inducers increased the expression of podocyte-ChAT and acetylcholine production. CONCLUSIONS These findings suggest de novo synthesis of acetylcholine by podocytes protected against inflammation and glomerular endothelium damage in anti-GBM glomerulonephritis.

中文翻译：

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足细胞产生乙酰胆碱及其对 GN 肾损伤的保护。


背景 调节内皮健康的最重要因素之一是乙酰胆碱，虽然它与胆碱能神经递质有关;它也由非神经元细胞表达。然而，它在肾脏中的作用仍然未知，因为肾脏不接受胆碱能神经支配。方法 为了确定乙酰胆碱是否在肾脏中产生，我们使用了 ChAT （BAC）-EGFP （ChAT 小鼠） 转基因小鼠，其中增强绿色荧光蛋白 （eGFP） 在内源性胆碱乙酰转移酶 （ChAT） 转录调节元件的控制下表达。然后，我们通过在 ChAT 转基因小鼠中诱导抗肾小球基底膜肾小球肾炎 （anti-GBM GN） 来研究乙酰胆碱在肾脏疾病中的作用。结果我们证明 ChAT 是唯一负责乙酰胆碱产生的酶，在肾小球足细胞中表达并产生乙酰胆碱。我们还显示，在 ChAT 转基因小鼠的抗 GBM GN 期间，ChAT 表达在肾小球中被诱导，主要在足细胞中，并保护小鼠免受肾损伤，肾小球增殖/纤维蛋白样坏死 （71%）、新月体形成 （98%） 和肾小管损伤 （78%）。相比之下，足细胞 ChAT 的特异性敲除使疾病的严重程度恶化。保护机制包括减少炎症、减弱血管生成因子减少和 eNOS 表达增加。体外和体内研究表明，胆碱酯酶抑制剂和 ChAT 诱导剂等可用药物可增加足细胞-ChAT 的表达和乙酰胆碱的产生。结论 这些发现表明，在抗 GBM 肾小球肾炎中，足细胞对乙酰胆碱的从头合成可防止炎症和肾小球内皮损伤。