Podocyte loss is a detrimental feature and major cause of proteinuria in diabetic nephropathy (DN). Our previous study revealed that hepatocyte growth factor (HGF) prevented high glucose-induced podocyte injury via enhancing autophagy. In the current study, we aimed to assess the role of HGF on podocyte homeostasis in DN and clarify its mechanisms further. Diabetic mice treated with HGF had markedly reduced ratio of kidney weight to body weight, urinary albumin excretion, podocyte loss and matrix expansion compared with that in the non-treated counterpart. Simultaneously, HGF-treated diabetic mice exhibited increased autophagy activity as indicated by the decreased accumulation of sequestosome 1 (SQSTM1/ p62) and increased microtubule-associated proteins 1 light chains 3 (LC3) II/LC3I ratio. These beneficial effects of HGF were blocked by HGF/c-Met inhibitor Crizotinib or phosphatidylinositide 3-kinases (PI3K) inhibitor LY294002. Moreover, HGF treatment obviously prevented inactivation of the protein kinase B (Akt)-glycogen synthase kinase 3 beta (GSK3β)-transcription factor EB (TFEB) axis in high glucose-stimulated podocytes, which was associated with improved lysosome function and autophagy. Accordingly, adenovirus vector encoding constitutively active GSK3β (Ad-GSK3β-S9A) offset whereas small interfering RNA against GSK3β (GSK3β siRNA) recapitulated salutary effects of HGF on lysosome number and autophagy in podocytes. These results suggested that HGF protected against diabetic nephropathy through restoring podocyte autophagy, which at least partially involved PI3K/Akt-GSK3β-TFEB axis-mediated lysosomal function improvement.

足细胞丢失是糖尿病肾病 (DN) 中蛋白尿的不利特征和主要原因。我们之前的研究表明，肝细胞生长因子 (HGF) 通过增强自噬来预防高糖诱导的足细胞损伤。在目前的研究中，我们旨在评估 HGF 对 DN 足细胞稳态的作用并进一步阐明其机制。与未处理的对应物相比，用 HGF 处理的糖尿病小鼠肾脏重量与体重的比率、尿白蛋白排泄、足细胞损失和基质膨胀显着降低。同时，HGF 治疗的糖尿病小鼠表现出增加的自噬活性，如 sequestosome 1 (SQSTM1/p62) 的积累减少和微管相关蛋白 1 轻链 3 (LC3) II/LC3I 比率增加所示。HGF 的这些有益作用被 HGF/c-Met 抑制剂克唑替尼或磷脂酰肌醇 3-激酶 (PI3K) 抑制剂 LY294002 阻断。此外，HGF 处理明显阻止了高糖刺激足细胞中蛋白激酶 B (Akt)-糖原合酶激酶 3 β (GSK3β)-转录因子 EB (TFEB) 轴的失活，这与溶酶体功能和自噬的改善有关。因此，编码组成型活性 GSK3β（Ad-GSK3β-S9A）的腺病毒载体抵消了 GSK3β 的小干扰 RNA（GSK3β siRNA），概括了 HGF 对足细胞溶酶体数量和自噬的有益作用。这些结果表明 HGF 通过恢复足细胞自噬来预防糖尿病肾病，这至少部分涉及 PI3K/Akt-GSK3β-TFEB 轴介导的溶酶体功能改善。