The cross‐talk between RAGE and DIAPH1 in neurological complications of diabetes: A review

Abstract

Neuropathy, or dysfunction of peripheral nerve, is one of the most common neurological manifestation in patients with diabetes mellitus (DM). DM is typically associated with a hyperglycaemic milieu, which promotes non‐enzymatic glycation of proteins. Proteins with advanced glycation are known to engage a cell‐surface receptor called the receptor for advanced glycation end products (RAGE). Thus, it is reasonable to assume that RAGE and its associated molecule‐mediated cellular signalling may contribute to DM‐induced symmetrical axonal (length‐dependent) neuropathy. Of particular interest is diaphanous related formin 1 (DIAPH1), a cytoskeletal organizing molecule, which interacts with the cytosolic domain of RAGE and whose dysfunction may precipitate axonopathy/neuropathy. Indeed, it has been demonstrated that both RAGE and DIAPH1 are expressed in the motor and sensory fibres of nerve harvested from DM animal models. Although the detailed molecular role of RAGE and DIAPH1 in diabetic neurological complications remains unclear, here we will discuss available evidence of their involvement in peripheral diabetic neuropathy. Specifically, we will discuss how a hyperglycaemic environment is not only likely to elevate advanced glycation end products (ligands of RAGE) and induce a pro‐inflammatory environment but also alter signalling via RAGE and DIAPH1. Further, hyperglycaemia may regulate epigenetic mechanisms that interacts with RAGE signalling. We suggest the cumulative effect of hyperglycaemia on RAGE–DIAPH1‐mediated signalling may be disruptive to axonal cytoskeletal organization and transport and is therefore likely to play a key role in pathogenesis of diabetic symmetrical axonal neuropathy.

Complete loss of the X-linked geneCASKcauses severe cerebellar degeneration

“…On staining the Bergmann glia with S100β, we did not see increased immunoreactivity in Bergmann glia or proliferation of Bergmann glia (figure 5C,F), but we did observe a strong trend of increased S100β reactivity in the IGL extracellular space (figure 5D,E). S100β is known to be secreted during metabolic stress and functions via binding to a receptor of advanced glycation end products 56 57. Overall, this finding suggests that CASK loss-of-function produces protracted neuronal loss in the cerebellum, explaining why MICPCH in humans typically becomes obvious a few months after birth.…”

Pathophysiology of RAGE in inflammatory diseases

“…In addition, DIAPH1 is required as a RAGE bridging protein for active signaling and molecular pathways in a variety of vascular and inflammatory cells, such as endothelial cells, smooth muscle cells, and macrophages (3,99,100). Evidence suggests that the interaction of ctRAGE with DIAPH1 is critical for intracellular signaling such as AKT phosphorylation and the JAK/STAT signaling cascade (101)(102)(103). (Figure 1).…”

“…In addition, increased expression of HMGB1 and RAGE in diabetic peripheral neuropathy (117). The interaction analysis using GeneMANIA software suggests that HMGB1-RAGE-DIAPH1 interaction may be critical for the progression of diabetic peripheral neuropathy (103).…”

The receptor for advanced glycation end products and its ligands’ expression in OVE26 diabetic sciatic nerve during the development of length‐dependent neuropathy

“…[9][10][11] Moreover, the S100B is present in the serum of patients with diabetes; hence, RAGE-S100B cross-talk may play a crucial role in the progression of DLDN. [6][7][12][13][14] Consequently, our previous studies revealed that the expression of S100B protein was elevated in porcine hyperglycemic sciatic nerve. 12 However, recent data on DLDN pathogenesis have revealed that another player, diaphanous-related formin 1 (DIAPH1) [7][8][9][10][11][15][16] , an intracellular cytoplasmic ligand of RAGE, might be involved.…”

“…Until now, evidence indicated that a variety of factors, such as local neuroinflammation, malfunctions in cytoskeleton remodeling, impaired axonal transport, and enhanced oxidative stress, might be involved in the progression of LDN in patients suffering from diabetes. [6][7][8][9][10][11] Advanced glycation end products (AGEs) are the products of nonenzymatic glycation and oxidation of proteins and lipids. AGEs may accumulate in different biological locations, such as the peripheral nervous system (PNS).…”