RAGE-Induced Cytosolic ROS Promote Mitochondrial Superoxide Generation in Diabetes

Abstract

Damaged mitochondria generate an excess of superoxide, which may mediate tissue injury in diabetes. We hypothesized that in diabetic nephropathy, advanced glycation end-products (AGEs) lead to increases in cytosolic reactive oxygen species (ROS), which facilitate the production of mitochondrial superoxide. In normoglycemic conditions, exposure of primary renal cells to AGEs, transient overexpression of the receptor for AGEs (RAGE) with an adenoviral vector, and infusion of AGEs to healthy rodents each induced renal cytosolic oxidative stress, which led to mitochondrial permeability transition and deficiency of mitochondrial complex I. Because of a lack of glucose-derived NADH, which is the substrate for complex I, these changes did not lead to excess production of mitochondrial superoxide; however, when we performed these experiments in hyperglycemic conditions in vitro or in diabetic rats, we observed significant generation of mitochondrial superoxide at the level of complex I, fueled by a sustained supply of NADH. Pharmacologic inhibition of AGE-RAGE-induced mitochondrial permeability transition in vitro abrogated production of mitochondrial superoxide; we observed a similar effect in vivo after inhibiting cytosolic ROS production with apocynin or lowering AGEs with alagebrium. Furthermore, RAGE deficiency prevented diabetes-induced increases in renal mitochondrial superoxide and renal cortical apoptosis in mice. Taken together, these studies suggest that AGE-RAGE-induced cytosolic ROS production facilitates mitochondrial superoxide production in hyperglycemic environments, providing further evidence of a role for the advanced glycation pathway in the development and progression of diabetic nephropathy.

Multiple levels of regulation determine the role of the receptor for AGE (RAGE) as common soil in inflammation, immune responses and diabetes mellitus and its complications

“…Experiments using in vitro produced, highly modified AGE albumin provide evidence that the cytoplasmic domain possibly interacts with diaphanous-1 and transduces the extracellular signals evoked into cellular signalling through activation the rho-GTPases RAC-1 and CDC42, reorganisation of the actin cytoskeleton, regulation of cell motility and migration [62]. Future studies, however, should show whether physiological ligand activation and/or cell-specific regulation mechanisms exist for the proposed RAGE-mediated multiple cellular signalling cascades, including RAC-1 and CDC42, NADPH-oxidase, ERK1/2(p44/p42)-, p38-and SAPK/JNK-MAP-kinases, phosphoinositol-3-kinase and the JAK/STAT pathway [8,15,17,63]. A critical review of published data defining RAGE-dependent signalling pathways reveals that only a few approaches have studied those time points (e.g.…”

“…When Rage −/− mice were generated [10][11][12] and studied in different pathologies, it became apparent that RAGE is involved in a number of diseases of the innate immune system and RAGE was redefined as a promiscuous pattern recognition receptor (PRR), mediating immune and inflammatory responses, promotion and progression of cancer [13,14], and micro-as well as macrovascular disease [2][3][4][5] by binding a variety of ligands released by inflammatory, stressed and damaged cells [8,15,16]. Subsequently, RAGE×ligand interaction has been associated with survival of RAGE-producing cells, production of cellular reactive oxygen species (ROS), increased levels of phosphorylated extracellular signal-regulated kinase (ERK)1/2, new synthesis of p65 (also known as RelA), NF-κB activation and sustained inflammation [8,15,17,18]. RAGE activation of these cellular pathways is supposed to contribute to diabetes as well as to its complications.…”

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis

“…There is increasing evidence to indicate that the disruption of mitochondrial bioenergetics, which leads to altered capacity for ATP production, may contribute to the development and progression of chronic kidney disease (CKD) (2,3). This includes in the setting of diabetic nephropathy (DN) (4)(5)(6)(7)(8)(9)(10), but the specific molecular mechanisms linking mitochondrial dysfunction to CKD remain to be elucidated.…”

E2F1-dependent miR-421 regulates mitochondrial fragmentation and myocardial infarction by targeting Pink1

“…Heart failure is the common end stage of cardiovascular diseases and represents a decline in cardiac function. Heart failure involves the impairment of cardiomyocytes in energy metabolism, calcium homeostasis, reactive oxygen species production and cell death [2][3][4] . Since mitochondria are the major ATP and reactive oxygen species production organelle in cardiomyocytes, mitochondrial malfunction is tightly related to cardiovascular diseases and contributes to heart failure.…”