Glomerular matrix protein accumulation, mediated largely by mesangial cells, is central to the pathogenesis of diabetic kidney disease. Our previous studies showed that the membrane microdomains caveolae and their marker protein caveolin-1 regulate matrix protein synthesis in mesangial cells in response to diabetogenic stimuli, and that caveolin-1 knockout mice are protected against diabetic kidney disease. In a screen to identify the molecular mechanism underlying this protection, we also established that secreted antifibrotic glycoprotein follistatin is significantly upregulated by caveolin-1 deletion. Follistatin potently neutralizes activins, members of the transforming growth factor–β superfamily. A role for activins in diabetic kidney disease has not yet been established. Therefore, in vitro, we confirmed the regulation of follistatin by caveolin-1 in primary mesangial cells and showed that follistatin controls both basal and glucose-induced matrix production through activin inhibition. In vivo, we found activin A upregulation by immunohistochemistry in both mouse and human diabetic kidney disease. Importantly, administration of follistatin to type 1 diabetic Akita mice attenuated early diabetic kidney disease, characterized by albuminuria, hyperfiltration, basement membrane thickening, loss of endothelial glycocalyx and podocyte nephrin, and glomerular matrix accumulation. Thus, activin A is an important mediator of high glucose–induced profibrotic responses in mesangial cells, and follistatin may be a potential novel therapy for the prevention of diabetic kidney disease.

肾小球基质蛋白的积累主要由肾小球膜细胞介导，对糖尿病肾病的发病机制至关重要。我们以前的研究表明，膜微区海绵体及其标记蛋白caveolin-1调节系膜细胞对糖尿病形成刺激的响应，并保护caveolin-1基因敲除小鼠免受糖尿病性肾脏疾病的侵害。在鉴定该保护基础的分子机制的屏幕中，我们还确定了分泌的抗纤维化糖蛋白卵泡抑素可通过Caveolin-1缺失显着上调。卵泡抑素有效地中和了激活素，激活素是转化生长因子β超家族的成员。激活素在糖尿病性肾脏疾病中的作用尚未确定。因此，体外，我们证实了caveolin-1在原代肾小球系膜细胞中对卵泡抑素的调节，并表明卵泡抑素通过激活素抑制来控制基础和葡萄糖诱导的基质产生。在体内，我们通过小鼠和人类糖尿病性肾脏疾病的免疫组织化学发现了激活素A的上调。重要的是，对1型糖尿病Akita小鼠施用卵泡抑素可减轻早期糖尿病肾脏疾病，其特征为蛋白尿，超滤，基底膜增厚，内皮糖萼和足细胞肾素的损失以及肾小球基质的蓄积。因此，激活素A是肾小球系膜细胞中高葡萄糖诱导的纤维化反应的重要介质，卵泡抑素可能是预防糖尿病肾病的潜在新疗法。