Evidence is accruing that the AGE-RAGE pathway plays critical roles in the pathogenesis of DN. We hypothesize that AGEs, via RAGE, impact on multiple distinct cell types implicated in nephropathy. Experimental evidence supports the premise in vitro and in vivo that AGE-RAGE interaction in podocytes results in upregulation of VEGF, and, thereby, a mechanism to attract inflammatory cells and release of pro-inflammatory RAGE ligands, such as S100/calgranulins and HMGB1. In addition, ligand-RAGE interaction activates MCs, thereby providing a mechanism to augment generation of proscle-rotic growth factors and cytokines such as TGF-p. RAGE is also expressed by endothelial cells, thus, interaction of RAGE ligands with RAGE in the endothelium may directly amplify vascular perturbation in the glomerulus. A key consequence of such injury is the development of albuminuria. Future studies must dissect the potential impact of inflammatory RAGE signaling in the pathogenesis of nephropathy.

Although studies in proximal tubular cells suggest roles for AGE-RAGE signaling in epithelial myofibroblast transdifferentiation, such concepts have yet to be explored in vivo and thus represent solely theoretical considerations at this time.

We conclude that future clinical trials should include studies focused on combination therapy strategies to target the AGE-RAGE axis. Importantly, the critical impact of stringent control of hyperglycemia is the foremost goal. Studies in the Diabetes Control and Complications (DCCT) research group clearly indicated that rigorous control of hyperglycemia was associated with decreased microvascular complications, including nephropathy (79). Recently, fascinating findings published by the Epidemiology of Diabetes Interventions and Complications (EDIC) study suggested that subjects in the original intensively treated DCCT group continued to display renoprotection (decreased albuminuria, hypertension, and rise in serum creatinine level) vs subjects originally in the conventional treatment group (80). This extended benefit occurred despite the fact that levels of glycosylated hemoglobin in the originally intensively treated subjects gradually became indistinguishable between the two groups. Such considerations suggest that earlier and substantive reduction in hyperglycemia in the original intensively treated group left an indelible mark in the vasculature of these diabetic subjects, and support the hypothesis that high levels of glucose may be linked to long-term "memory" in vascular targets in diabetes. It is plausible that AGE-RAGE interaction is one of the mechanisms underlying glycemic memory, thereby further supporting the targeting of this axis in chronic nephropathy.

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