Glucagon-like peptide-1 analog protects proximal tubules injury from lysosomal dysfunction and impaired autophagic flux

摘要

The role of glucagon-like peptide-1 analog (GLP-1) in autophagic flux and lysosomal dysfunction in obesity-related glomerulopathy (ORG) remains poorly understood. Here, we demonstrated that exposure to a high-fat diet (HFD) resulted in ectopic lipid accumulation, increased 24-hour urinary albumin, and vacuolated tubular cells. The apoptotic cell content in renal tubules was remarkably increased in the HFD group, compared to CON mice, as evident from TUNEL staining and caspase-3 expression, and significantly decreased upon switching to the normal chow diet and GLP-1 treatment. Compared to the control group, significant accumulation of Oil red O staining and CD36 and PLIN2 was observed in tubular cells of HFD mice. In the HFDG and HFD-C groups, lipid droplet deposition in tubular cells were inhibited. LC3 and p62 levels were markedly increased in proximal tubules of HFD mice, and palmitic acid impaired autophagic flux in HK2 cells. Electron microscopy revealed that non-functional lysosomal residue merged with the functional lysosome in the HFD group. GLP-1 treatment and a normal chow diet led to inhibition of enlarged lysosomal residue and restored autophagic flux. In conclusion, impaired lysosome and autophagic flux may be ameliorated by GLP-1 treatment and replacement with a normal chow diet.