Glomerular fibrosis now all the RAGE

Oldfield et al. have identified a crucial pathological role for the multifaceted receptor RAGE ? the receptor for advanced glycation end products (AGEs). AGEs form spontaneously when reducing sugars react with lysine residues on extracellular proteins. Even in healthy individuals, they accumulate inexorably during aging, but this progression is particularly swift in diabetics, reflecting the higher glucose levels in their tissues during periods of hyperglycemia. Activation of RAGE by these ligands is associated with several disorders, and Oldfield and colleagues now propose that tubulointerstitial disease, a form of diabetic nephropathy, should be added to this list. The cell-type transformation, or trans-differentiation, of normal kidney epithelial cells to collagen-secreting myofibroblasts, is thought to drive this disease process. The authors show that RAGE signaling is required to induce trans-differentiation in cultured kidney cells and rat kidney tissue, and probably also in the diabetic human kidney. In the rat system, a drug that removes sugar adducts on proteins prevents trans-differentiation. This treatment also limits the secretion of TGF-b, which appears to mediate the effects of RAGE signaling on the phenotype of kidney cells. Consistent with this model, Oldfield et al. note that another inhibitor of AGE formation has also been reported to suppress RAGE-dependent activation of TGF-b in diabetic animals.

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