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Updated: Aug 26, 2026
Comparative Proteomic Analysis of Whole Kidney, Medulla, and Cortical Tubules in Diabetic Pathogenesis of Kidney Injury in Mice
Published on: May 2, 2025
Advanced glycation end products increase collagen-specific chaperone protein in mouse diabetic nephropathy
Seiji Ohashi1, Hideharu Abe, Toshikazu Takahashi
1Department of Clinical Biology and Medicine, Course of Biological Medicine, School of Medicine, The University of Tokushima, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Abstract:
Advanced glycation end products (AGEs) appear to contribute to the diabetic complications. This study reports the inhibitory effect of OPB-9195 (OPB), an inhibitor of AGEs formation, and the role of a collagen-specific molecular chaperone, a 47-kDa heat shock protein (HSP47) in diabetic nephropathy. Transgenic mice carrying nitric-oxide synthase cDNA fused with insulin promoter (iNOSTg) leads to diabetes mellitus. The iNOSTg mice at 6 months of age represented diffuse glomerulosclerosis, and the expression of HSP47 was markedly increased in the mesangial area in parallel with increased expression of types I and IV collagens. OPB treatment ameliorated glomerulosclerosis in the iNOSTg mice associated with the decreased expression of HSP47 and types I and IV collagens. The expression of transforming growth factor-beta (TGF-beta) was increased in glomeruli of iNOSTg mice and decreased after treatment with OPB. To confirm these mechanisms, cultured mesangial cells were stimulated with AGEs. AGEs significantly increased the expression of HSP47, type IV collagen, and TGF-beta mRNA. Neutralizing antibody for TGF-beta inhibited the overexpression of both HSP47 and type IV collagen in vitro. In conclusion, AGEs increase the expression of HSP47 in association with collagens, both in vivo and in vitro. The processes may be mediated by TGF-beta.
Insights
Advanced glycation end products (AGEs) contribute to diabetic complications. Inhibiting AGEs formation with OPB-9195 (OPB) reduced kidney damage by decreasing collagen and HSP47 expression, potentially mediated by TGF-beta.
Area of Science:
- Nephrology
- Endocrinology
- Molecular Biology
Background:
- Advanced glycation end products (AGEs) are implicated in diabetic complications.
- Diabetic nephropathy is characterized by glomerulosclerosis and increased collagen deposition.
- Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone involved in extracellular matrix production.
Purpose of the Study:
- To investigate the inhibitory effect of OPB-9195 (OPB) on AGEs formation in diabetic nephropathy.
- To elucidate the role of HSP47 in AGEs-induced kidney damage.
- To explore the involvement of transforming growth factor-beta (TGF-beta) in these processes.
Main Methods:
- Utilized transgenic mice (iNOSTg) exhibiting diabetes and glomerulosclerosis.
- Administered OPB-9195 to diabetic mice and assessed kidney pathology, collagen, HSP47, and TGF-beta expression.
- Stimulated cultured mesangial cells with AGEs and evaluated the effects of OPB and TGF-beta neutralizing antibodies.
Main Results:
- OPB treatment ameliorated glomerulosclerosis in diabetic mice, decreasing HSP47 and collagen (types I and IV) expression.
- AGEs stimulation in vitro increased HSP47, type IV collagen, and TGF-beta mRNA expression in mesangial cells.
- TGF-beta neutralizing antibodies inhibited AGEs-induced overexpression of HSP47 and type IV collagen in vitro.
Conclusions:
- AGEs promote HSP47 expression, contributing to collagen accumulation in diabetic nephropathy.
- OPB-9195 effectively inhibits AGEs formation and mitigates kidney damage.
- TGF-beta plays a mediating role in AGEs-induced HSP47 and collagen overexpression.
