Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of <i>Atg5</i> specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelial-specific deletion of <i>Atg5</i> also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.

肾小球（glomerulus）是高度特化的毛细血管袢，可在压力驱动下将大量水分与小分子溶质滤入肾小囊腔，同时保留白蛋白与大分子蛋白质。肾小球滤过屏障（glomerular filtration barrier, GFB）是血液与尿液之间的高度特化滤过界面，对血浆中的中小分子溶质具有高通透性，但对白蛋白这类大分子物质相对不通透。GFB的完整性由其三层结构间的分子相互作用维持：肾小球内皮细胞、肾小球基底膜，以及构成GFB外层的高度特化有丝分裂后周细胞——足细胞（podocytes）。肾小球超滤异常会引发蛋白尿与进行性肾功能不全，这凸显了GFB的重要性。事实上，白蛋白尿可强烈预测慢性肾病的病程，尤其是作为肾功能不全主要病因的糖尿病肾病（diabetic nephropathy, DN）。本研究发现，高葡萄糖浓度可促进足细胞培养体系中的自噬流（autophagy flux），且糖尿病小鼠的足细胞内LC3B II的表达水平升高。特异性敲除足细胞中的Atg5基因，可加速糖尿病诱导的足细胞病进展，伴随GFB漏出与肾小球硬化。值得注意的是，对GFB另一侧的内皮细胞层进行自噬相关遗传干预——即特异性敲除内皮细胞中的Atg5基因——同样会导致毛细血管稀疏与糖尿病肾病进展加速。综上，自噬是GFB两层细胞层的关键保护机制，提示自噬可作为糖尿病肾病极具前景的新型治疗策略。