AGEs induce oxidative stress and activate protein kinase C-β_IIin neonatal mesangial cells

Abstract

Increased activation of specific protein kinase C (PKC) isoforms and increased nonenzymatic glycation of intracellular and extracellular proteins [the accumulation of advanced glycation end products (AGEs)] are major mechanistic pathways implicated in the pathogenesis of diabetic complications. Blocking PKC-beta(II) has been shown to decrease albuminuria in animal models of diabetes. To demonstrate a direct relationship between AGEs and the induction and translocation of PKC-beta(II), studies were carried out in rat neonatal mesangial cells, known to express PKC-beta(II) in association with rapid proliferation in post-natal development. Oxidative stress was studied by using the fluorescent probe dichlorfluorescein diacetate. Translocation of PKC-beta(II) was demonstrated by using immunofluorescence and Western blotting of fractionated mesangial cells. Induction of intracellular oxidative stress, increase in intracellular calcium, and cytosol to membrane PKC-beta(II) translocation (with no change in PKC-alpha) were demonstrated after exposure to AGE-rich proteins. These data support the hypothesis that AGEs cause mesangial oxidative stress and alterations in PKC-beta(II), changes that may ultimately contribute to phenotypic abnormalities associated with diabetic nephropathy.

Advanced glycation end-products: a review

“…Oxidants such as the superoxide anion, hydrogen peroxide and lipid peroxides cause damage by oxidation, fragmentation and cross-linking [25]. Formation of AGE also induces free-radical production as well as depleting nitric oxide concentrations [28], leading to oxidative stress [102,103]. As nitric oxide is vasodilatory and has antiproliferative effects on vascular smooth muscle [25], AGE accumulation could therefore result in vascular thickening with loss of elasticity, hypertension and endothelial dysfunction (Table 1).…”

Changes in the Expression of Nephrin Gene and Protein in Experimental Diabetic Nephropathy

“…Interestingly, the changes in GBM, including an increase in type IV collagen and fibronectin, may be caused directly by hyperglycemia, increase of reactive oxygen species, and nonenzymatic glycosylation (Odoni and Ritz, 1999). These changes are associated with the activation of protein kinase C (PKC), which is believed to mediate many of the manifestations of diabetic nephropathy (Koya and King, 1998;Scivittaro et al, 2000;Suzuki and Miyata, 1999). Our results show that activation of PKC causes substantial increase of nephrin mRNA and respective protein production in cultured cells expressing nephrin (Wang et al, 2001).…”

Glucosamine-Induced Endoplasmic Reticulum Dysfunction Is Associated With Accelerated Atherosclerosis in a Hyperglycemic Mouse Model

“…AGEs induce intracellular inflammatory and oxidative stress pathways through interactions with receptors for AGEs (RAGEs) (4). Protein kinase C can be activated by AGE-RAGE interactions, resulting in proatherogenic consequences, including disruption of vascular structure and response as well as enhanced inflammatory gene expression (5,6). However, the apparent inability of antioxidant supplementation to reduce cardiovascular events in diabetic patients suggests that alternative mechanisms of hyperglycemia-induced atherosclerosis may also contribute to the progression of atherosclerosis (7)(8)(9)(10).…”