Advanced Glycation End Products Increase Collagen-specific Chaperone Protein in Mouse Diabetic Nephropathy

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-␤ (TGF-␤) 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-␤ mRNA. Neutralizing antibody for TGF-␤ 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-␤.

Transforming growth factor-β induces cellular injury in experimental diabetic neuropathy

“…TGF-β has been clearly implicated in the pathogenesis of one microvascular complication, diabetic nephropathy, and has been shown to promote renal cell hypertrophy and stimulate formation of extra cellular matrix in the kidney (Ohashi et al, 2004); Gore-Hyer et al, 2002;Kim et al, 2001;Park et al, 1997;Sharma et al, 1997). It also has been shown that overeexpression of TGF-β in diabetic rat glomeruli promotes extra cellular matrix accumulation that is responsible for glomerular injury, and treatment with anti-TGF-β antibody ameliorates diabetic nephropathy (Hill et al, 2001;Ma et al, 2004).…”

“…It also has been shown that overeexpression of TGF-β in diabetic rat glomeruli promotes extra cellular matrix accumulation that is responsible for glomerular injury, and treatment with anti-TGF-β antibody ameliorates diabetic nephropathy (Hill et al, 2001;Ma et al, 2004). In previous tissue culture and animal studies, cellular matrix production was stimulated by high glucose levels, was associated with increased TGF-β expression, and the matrix stimulatory effects of high glucose were prevented by anti-TGF-β therapy (Gore-Hyer et al, 2002;Kim et al, 2001;Ohashi et al, 2004;Park et al, 1997;Sharma et al, 1997). Despite a strong association of TGF-β with renal disease no association with neuropathy has so far been established.…”

Elevation of pancreatic oxidative stress in STR/Ort mice

“…Although the presence of HSP32 could be detected in the pancreas of STR/ Ort mice, the protein was not detected in '/db mice. Previous studies have reported that the levels of oxidative stress markers HSP32 and HSP47 are elevated in diabetic mouse models (Gorogawa 2002;Ohashi 2004). The expression of HSP32 and HSP47 can also be elevated in response to ROS (Yu and Moriniere 2009).…”

Significance of Advanced Glycation End-Products (AGE) and the Receptor for AGE (RAGE) in Diabetic Nephropathy

“…4). The sole iNOS Tg mice also showed progression of diabetic nephropathy accompanied by expression of TGF- in glomeruli (47). Inagi and our group introduced megsin (mesangial cell-specific gene with homology to serine protease inhibitor) as the third transgene into RAGE-iNOS double Tg mice, this resulting in further acceleration of the development of nephropathy signs such as mesangial expansion, nodule-like lesion, and tubulointerstitial damage with an increase in local oxidative stress (48).…”