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Controlling the receptor for advanced glycation end-products to conquer diabetic vascular complications.

Yamamoto Y, Yamamoto H - J Diabetes Investig (2012)

Bottom Line: Receptor-dependent mechanisms are involved in AGE-induced cellular dysfunction and tissue damage.The receptor for AGE (RAGE), originally an AGE-binding receptor, is now recognized as a member of pattern-recognition receptors and a pro-inflammatory molecular device that mediates danger signals to the body.Previous animal studies have shown RAGE dependent of diabetic vascular injuries.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

ABSTRACT
Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long-term diabetes. Extensive intracellular and extracellular formation of advanced glycation end-products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor-dependent mechanisms are involved in AGE-induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE-binding receptor, is now recognized as a member of pattern-recognition receptors and a pro-inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00191.x, 2012).

No MeSH data available.


Related in: MedlinePlus

 Phenotypes of diabetic nephropathy in receptor for advanced glycation end‐products (RAGE) gene‐manipulated mice. KO, knockout mice; Tg, transgenic mice.
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f3:  Phenotypes of diabetic nephropathy in receptor for advanced glycation end‐products (RAGE) gene‐manipulated mice. KO, knockout mice; Tg, transgenic mice.

Mentions: To evaluate whether RAGE and the multiligand system participate in the development of diabetic vascular complications, we created transgenic mice that overexpress human RAGE proteins in endothelial cells, and crossbred them with another transgenic mouse line that develops insulin‐dependent diabetes shortly after birth55,56. The resultant double transgenic mice showed significant increases in kidney weight, albuminuria, glomerulosclerosis and serum creatinine compared with the diabetic controls (Figure 3)56,57. Triple transgenic mice overexpressing RAGE, inducible nitric oxide (NO) synthase and megsin developed severe diabetic nephropathy as early as 16 weeks after birth, characterized by the development of mesangial expansion, nodule‐like lesions and tubulointerstitial damage with an increase in local oxidative stress (Figure 3)58. In addition, indices diagnostic of diabetic retinopathy were most prominent in double transgenic mice57. Kaji et al.59 showed blood–retinal barrier breakdown and increased leukostasis in RAGE‐overexpressing mice; these were ameliorated by treatment with soluble RAGE (sRAGE). Furthermore, we generated RAGE‐knockout (KO) mice and report the marked improvement in nephromegaly, albuminuria and glomerulosclerosis, as well as increased serum creatinine levels in diabetic RAGE‐KO mice (Figure 3)31. The deletion of RAGE also attenuated the endothelial–mesenchymal transition60. Streptozotocin (STZ)‐injected RAGE‐KO mice were protected from early kidney injuries as a result of mesangial matrix expansion and thickening of the glomerular basement membrane as seen in wild‐type diabetic mice61. Furthermore, RAGE deletion also improved diabetic nephropathy seen in OVE26 type 1 diabetic mice with progressive glomerulosclerosis and declining renal function62.


Controlling the receptor for advanced glycation end-products to conquer diabetic vascular complications.

Yamamoto Y, Yamamoto H - J Diabetes Investig (2012)

 Phenotypes of diabetic nephropathy in receptor for advanced glycation end‐products (RAGE) gene‐manipulated mice. KO, knockout mice; Tg, transgenic mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4020727&req=5

f3:  Phenotypes of diabetic nephropathy in receptor for advanced glycation end‐products (RAGE) gene‐manipulated mice. KO, knockout mice; Tg, transgenic mice.
Mentions: To evaluate whether RAGE and the multiligand system participate in the development of diabetic vascular complications, we created transgenic mice that overexpress human RAGE proteins in endothelial cells, and crossbred them with another transgenic mouse line that develops insulin‐dependent diabetes shortly after birth55,56. The resultant double transgenic mice showed significant increases in kidney weight, albuminuria, glomerulosclerosis and serum creatinine compared with the diabetic controls (Figure 3)56,57. Triple transgenic mice overexpressing RAGE, inducible nitric oxide (NO) synthase and megsin developed severe diabetic nephropathy as early as 16 weeks after birth, characterized by the development of mesangial expansion, nodule‐like lesions and tubulointerstitial damage with an increase in local oxidative stress (Figure 3)58. In addition, indices diagnostic of diabetic retinopathy were most prominent in double transgenic mice57. Kaji et al.59 showed blood–retinal barrier breakdown and increased leukostasis in RAGE‐overexpressing mice; these were ameliorated by treatment with soluble RAGE (sRAGE). Furthermore, we generated RAGE‐knockout (KO) mice and report the marked improvement in nephromegaly, albuminuria and glomerulosclerosis, as well as increased serum creatinine levels in diabetic RAGE‐KO mice (Figure 3)31. The deletion of RAGE also attenuated the endothelial–mesenchymal transition60. Streptozotocin (STZ)‐injected RAGE‐KO mice were protected from early kidney injuries as a result of mesangial matrix expansion and thickening of the glomerular basement membrane as seen in wild‐type diabetic mice61. Furthermore, RAGE deletion also improved diabetic nephropathy seen in OVE26 type 1 diabetic mice with progressive glomerulosclerosis and declining renal function62.

Bottom Line: Receptor-dependent mechanisms are involved in AGE-induced cellular dysfunction and tissue damage.The receptor for AGE (RAGE), originally an AGE-binding receptor, is now recognized as a member of pattern-recognition receptors and a pro-inflammatory molecular device that mediates danger signals to the body.Previous animal studies have shown RAGE dependent of diabetic vascular injuries.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.

ABSTRACT
Diabetic vascular complications, such as cardiovascular disease, stroke and microangiopathy, lead to high rates of morbidity and mortality in patients with long-term diabetes. Extensive intracellular and extracellular formation of advanced glycation end-products (AGE) is considered a causative factor in vascular injuries in diabetes. Receptor-dependent mechanisms are involved in AGE-induced cellular dysfunction and tissue damage. The receptor for AGE (RAGE), originally an AGE-binding receptor, is now recognized as a member of pattern-recognition receptors and a pro-inflammatory molecular device that mediates danger signals to the body. Previous animal studies have shown RAGE dependent of diabetic vascular injuries. Prophylactic and therapeutic strategies focusing on RAGE and its ligand axis will be of great importance in conquering diabetic vascular complications. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00191.x, 2012).

No MeSH data available.


Related in: MedlinePlus