Abstract
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.
Highlights
Podocyte loss is a detrimental feature and major cause of proteinuria in diabetic nephropathy (DN)
hepatocyte growth factor (HGF) treatment significantly prevented the loss of podocytes, which could be abrogated by Crizotinib (Criz), a specific inhibitor of HGF receptor
Matrix expansion and glycogen accumulation assessed by periodic acid–Schiff (PAS) staining were shown in the mesangial region of nontreated and HGF+Criztreated DN mice but not in HGF-treated diabetic mice and nondiabetic control mice (Fig. 1b)
Summary
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. We aimed to assess the role of HGF on podocyte homeostasis in DN and clarify its mechanisms further. Depletion of podocytes, which are the critical constituent of the glomerular filtration barrier, initiates and drives the progression of proteinuria towards DN[1]. Terminally differentiated podocytes have limited capacity of regeneration in response to injury. Podocytes possess a relatively high basal level of autophagy, which is crucial for its stress adaptation[2]. Autophagy impairment has been proposed as a major contributor to the pathogenesis of podocytopathy and proteinuria
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