Department of Medicine, McGill University Health Centre Research Institute, McGill University , Montreal, Quebec , Canada.
Kidney Research Centre, Department of Medicine, The Ottawa Hospital, University of Ottawa , Ottawa, Ontario , Canada.
Am J Physiol Renal Physiol. 2018 Oct 1;315(4):F954-F966. doi: 10.1152/ajprenal.00082.2018. Epub 2018 Jun 6.
Mutations in α-actinin-4 (actinin-4) result in hereditary focal segmental glomerulosclerosis (FSGS) in humans. Actinin-4 mutants induce podocyte injury because of dysregulation of the cytoskeleton and proteotoxicity. Injury may be associated with endoplasmic reticulum (ER) stress and polyubiquitination of proteins. We assessed if the chemical chaperone 4-phenylbutyrate (4-PBA) can ameliorate the proteotoxicity of an actinin-4 mutant. Actinin-4 K255E, which causes FSGS in humans (K256E in the mouse), showed enhanced ubiquitination, accelerated degradation, aggregate formation, and enhanced association with filamentous (F)-actin in glomerular epithelial cells (GECs). The mutant disrupted ER function and stimulated autophagy. 4-PBA reduced actinin-4 K256E aggregation and its tight association with F-actin. Transgenic mice that express actinin-4 K256E in podocytes develop podocyte injury, proteinuria, and FSGS in association with glomerular ER stress. Treatment of these mice with 4-PBA in the drinking water over a 10-wk period significantly reduced albuminuria and ER stress. Another drug, celastrol, which enhanced expression of ER and cytosolic chaperones in GECs, tended to reduce actinin-4 aggregation but did not decrease the tight association of actinin-4 K256E with F-actin and did not reduce albuminuria in actinin-4 K256E transgenic mice. Thus, chemical chaperones, such as 4-PBA, may represent a novel therapeutic approach to certain hereditary glomerular diseases.
α-辅肌动蛋白-4（actinin-4）中的突变会导致人类遗传性局灶节段性肾小球硬化症（FSGS）。由于细胞骨架和蛋白毒性的失调，actinin-4 突变体诱导足细胞损伤。损伤可能与内质网（ER）应激和蛋白质多泛素化有关。我们评估了化学伴侣 4-苯丁酸（4-PBA）是否可以改善 actinin-4 突变体的蛋白毒性。在人类中引起 FSGS 的 actinin-4 K255E（在小鼠中为 K256E）显示出增强的泛素化、加速降解、聚集形成以及与肾小球上皮细胞（GEC）中的丝状（F）-肌动蛋白的更紧密结合。该突变体破坏了 ER 功能并刺激了自噬。4-PBA 减少了 actinin-4 K256E 的聚集及其与 F-肌动蛋白的紧密结合。在足细胞中表达 actinin-4 K256E 的转基因小鼠会发展为足细胞损伤、蛋白尿和 FSGS，同时伴有肾小球 ER 应激。在为期 10 周的时间内，用 4-PBA 通过饮用水对这些小鼠进行治疗可显著减少白蛋白尿和 ER 应激。另一种药物 celastrol 增强了 GEC 中的 ER 和胞质伴侣的表达，它可以减少 actinin-4 的聚集，但不能减少 actinin-4 K256E 与 F-肌动蛋白的紧密结合，也不能减少 actinin-4 K256E 转基因小鼠的白蛋白尿。因此，化学伴侣，如 4-PBA，可能代表治疗某些遗传性肾小球疾病的一种新的治疗方法。
