Hepatocyte growth factor has a role in the amelioration of diabetic vascular complications via autophagic clearance of advanced glycation end products: Dispo85E, an HGF inducer, as a potential botanical drug.
The aim of this study was to evaluate the effect and elucidate the potential mechanism of the extract of rhizomes from Dioscorea alata L. cv. Phyto, Dispo85E, on accelerating the elimination of advanced glycation end products (AGEs) in vitro and in vivo. Primary mouse nonparenchymal cells (NPCs) were used to evaluate the drug effect on AGEs clearance and autophagic-lysosomal activity. In an animal study, we used AGEs-induced diabetic mice to evaluate the drug effect on AGEs-induced vascular complications. Our results indicated that Dispo85E enhanced the endocytosis and degradation activity of AGEs in hepatic NPCs. Furthermore, the hepatocyte growth factor (HGF) expression level was positively correlated with the clearance capacity of the AGEs in NPCs after Dispo85E treatment. In addition, the effects of Dispo85E on the degradation and uptake capability of (14)C-AGEs were abolished in the presence of an anti-HGF neutralizing antibody. We further demonstrated that recombinant mouse HGF could enhance the endocytosis and autophagic clearance of AGEs in NPCs. The in vivo data indicated that Dispo85E increased hepatic HGF messenger RNA expression levels and decreased serum AGEs level in diabetic mice. Moreover, the function of retina and kidneys was improved by Dispo85E treatment in AGEs-induced diabetic mice. These results suggest that HGF may have an important role in the elimination of AGEs. This study suggests that Dispo85E is a botanical drug with a novel mechanism that enhances the clearance of AGEs through HGF-induced autophagic-lysosomal pathway and is a candidate drug for the treatment of diabetic vascular complications.
Institute of Biopharmaceutical Science, School of Pharmaceutical Science, National Yang-Ming University, Taipei City 112, Taiwan, Republic of China.
Kang-Yung
KY
Peng
Lin-Yea
LY
Horng
Hui-Ching
HC
Sung
Hui-Chuan
HC
Huang
Rong-Tsun
RT
Wu
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects*; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000188:drug therapy / Q000473:pathology; D003930:Diabetic Retinopathy / Q000188:drug therapy / Q000473:pathology; D027742:Dioscorea / Q000737:chemistry*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008247:Lysosomes / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy; D010936:Plant Extracts / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D027343:Rhizome / Q000737:chemistry
D019138:Antibodies, Blocking; C559486:Dispo85E; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D010936:Plant Extracts; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor