Division of Nephrology, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
Physiological Sciences, Federal University of Espirito Santo, Vitoria, Brazil.
Kidney Int. 2019 Nov;96(5):1134-1149. doi: 10.1016/j.kint.2019.05.032. Epub 2019 Jun 17.
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，主要由系膜细胞介导，是糖尿病肾病发病机制的核心。我们之前的研究表明，膜微区 caveolae 及其标记蛋白 caveolin-1 调节系膜细胞中基质蛋白的合成，以响应致糖尿病刺激，并且 caveolin-1 敲除小鼠对糖尿病肾病有保护作用。在筛选鉴定这种保护作用的分子机制的过程中，我们还发现，分泌性抗纤维化糖蛋白 follistatin 被 caveolin-1 缺失显著上调。Follistatin 能强有力地中和激活素，转化生长因子-β超家族的成员。激活素在糖尿病肾病中的作用尚未确定。因此，在体外，我们在原代系膜细胞中证实了 follistatin 受 caveolin-1 的调节，并表明 follistatin 通过抑制激活素控制基础和葡萄糖诱导的基质产生。在体内，我们通过免疫组织化学发现在小鼠和人类糖尿病肾病中激活素 A 的上调。重要的是，向 1 型糖尿病 Akita 小鼠给予 follistatin 可减轻早期糖尿病肾病，其特征为蛋白尿、超滤、基底膜增厚、内皮糖萼和足细胞 nephrin 的丧失以及肾小球基质的积累。因此，激活素 A 是高葡萄糖诱导的系膜细胞中致纤维化反应的重要介质，而 follistatin 可能是预防糖尿病肾病的一种潜在的新型治疗方法。
