Susceptibility to Diabetic Nephropathy Is Related to Dicarbonyl and Oxidative Stress

Beisswenger, Paul J.; Drummond, Keith N.; Nelson, Robert G.; Howell, Scott K.; Szwergold, Benjamin S.; Mauer, Michael

doi:10.2337/diabetes.54.11.3274

Cited by 168 publications

(138 citation statements)

References 57 publications

Supporting

Mentioning

128

Contrasting

Unclassified

Order By: Relevance

“…Our observations that Glo1 overexpression reduced diabetes-induced vascular and renal dysfunction, as well as data from other studies [30,42,43], support a role for glycation in these pathogeneses. In addition, a cohort study by Beisswenger et al showed that progression of diabetic nephropathy is also significantly related to elevation in dicarbonyl stress [11]. In this study elevated levels of MGO correlated with loss of podocytes, another mechanism preceding glomerular leakage [44].…”

Section: Discussionmentioning

confidence: 53%

“…MGO is known to have detrimental effects on cellular function and it is also evident that elevated levels of MGO are responsible for renal oxidative stress, as demonstrated in diabetic rats [10]. Most importantly, progression of hypertension and diabetic nephropathy in humans is also significantly related to increased levels of MGO [11,12].…”

Section: Introductionmentioning

confidence: 95%

See 1 more Smart Citation

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis In diabetes, advanced glycation end-products (AGEs) and the AGE precursor methylglyoxal (MGO) are associated with endothelial dysfunction and the development of microvascular complications. In this study we used a rat model of diabetes, in which rats transgenically overexpressed the MGO-detoxifying enzyme glyoxalase-I (GLO-I), to determine the impact of intracellular glycation on vascular function and the development of early renal changes in diabetes. Methods Wild-type and Glo1 -overexpressing rats were rendered diabetic for a period of 24 weeks by intravenous injection of streptozotocin. Mesenteric arteries were isolated to study ex vivo vascular reactivity with a wire myograph and kidneys were processed for histological examination. Glycation was determined by mass spectrometry and immunohistochemistry. Markers for inflammation, endothelium dysfunction and renal dysfunction were measured with ELISA-based techniques. Results Diabetes-induced formation of AGEs in mesenteric arteries and endothelial dysfunction were reduced by Glo1 overexpression. Despite the absence of advanced nephrotic lesions, early markers of renal dysfunction (i.e. increasedElectronic supplementary material The online version of this article

show abstract

Section: Discussionmentioning

confidence: 53%

Section: Introductionmentioning

confidence: 95%

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

et al. 2013

View full text Add to dashboard Cite

show abstract

“…An important issue raised by our experiments deals with the contribution of Rac-1-mediated ROS production in EGFR activation as well as in the signaling cascade promoting MC cell cycle progression upon ox-LDL. Susceptibility to diabetic nephropathy mainly relies on oxidative stress (44), and increased levels of ROS in association with up-regulation of the gp91 phox and Rac-1 expression have been reported in diabetes (45). Thus, our data add further insight into the molecular mechanisms promoting early MC hypertrophy in diabetes-associated renal disease.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and β4 Integrin Expression

Dentelli

Rosso

Zeoli

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

Lipid abnormalities and oxidative stress, by stimulating mesangial cell (MC) proliferation, can contribute to the development of diabetes-associated renal disease. In this study we investigated the molecular events elicited by oxidized low density lipoproteins (ox-LDL) in MC. We demonstrate that in MC cultured in the presence of ox-LDL, survival and mitogenic signals on Akt and Erk1/2 MAPK pathways are induced, respectively. Moreover, as shown by the expression of the dominant negative Rac-1 construct, we first report that ox-LDL-mediated cell survival and cell cycle progression depend on Rac-1 GTPase-mediated reactive oxygen species production and on epidermal growth factor receptor transactivation. By silencing Akt and blocking Erk1/2 MAPK pathways, we also demonstrate that these signals are downstream to Rac-1/reactive oxygen species production and epidermal growth factor receptor activation. Finally, by endogenous depletion of ␤4 integrin, expressed in MC, we provide evidence that the expression of this adhesion molecule is essential for ox-LDL-mediated MC dysfunction. Our data identify a novel signaling pathway involved in oxidative stress-induced diabetes-associated renal disease and provide the rationale for therapeutically targeting ␤4 integrin.Abnormalities in lipoprotein metabolism are commonly observed in patients with renal disease. Specifically, hyperlipidemia and glomerular lipid deposition of atherogenic lipoproteins (low density lipoproteins (LDL), 2 and their oxidized variants, ox-LDL) are implicated in key pathobiological processes involved in the development of glomerular diseases, including mesangial cell (MC) hypercellularity (1). The relevance of mitogen intracellular signaling in mesangial proliferative disease has only recently been recognized (2). Indeed, accumulation of atherogenic lipoproteins within the glomerulus, by activating membrane receptor protein-tyrosine kinases (RPTK), such as the epidermal growth factor receptor (EGFR), triggers MAPK cascades leading to cyclin/cyclin-dependent kinase activation of DNA synthesis and MC proliferation (2). Moreover, in smooth muscle cells, ox-LDL (3) has been shown to trigger the phosphatidylinositol 3-kinase/Akt signaling pathway (4). These data thus suggest that atherogenic lipoproteins may act as one of the major endogenous modulators for mitogenic signaling response within the glomerulus.Although superoxide anions and hydrogen peroxide are generally considered to be toxic, recent evidence suggests that the production of the reactive oxygen species (ROS) might be an integral component of membrane receptor signaling (5). In mammalian cells, a vast array of intracellular stimuli have been shown to induce a transient increase in the intracellular ROS concentrations, and specific inhibition of ROS generation results in a complete blockage of stimulant-dependent signaling (5). In particular, growth factor-mediated ROS generation seems to be necessary for propagation of downstream mitogenic and antiapoptotic signals (5).Rho family GTPases are imp...

show abstract

“…MG-H1 residues are a major type of protein damage by glycation in diabetes, occurring on both cellular and extracellular proteins (20,21). Increased concentration of MG-H1 residues in plasma protein of diabetic patients was not linked directly to A1C (22), probably because methylglyoxal formation is increased in both fasting and postprandial hyperglycemia (16,23) and influenced by factors other than hyperglycemia (low glyceraldehyde-3-phosphate dehydrogenase activity [24]). MG-H1 residue formation occurred at susceptible hotspot sites in proteins with loss of functional activity (19).…”

mentioning

confidence: 99%

Increased Dicarbonyl Metabolism in Endothelial Cells in Hyperglycemia Induces Anoikis and Impairs Angiogenesis by RGD and GFOGER Motif Modification

Dobler

Ahmed²,

Song³

et al. 2006

Diabetes

244

224

View full text Add to dashboard Cite

Chronic vascular disease in diabetes isC hronic vascular disease is the major cause of morbidity and mortality in diabetes (1). This is associated with dysfunction of endothelial cells in hyperglycemia (2) and damage to the endothelium; the latter is indicated in vivo by increased detachment and premature death of endothelial cells by apoptosis (including anoikis) (3,4). A cellular marker of damage to the endothelium, increased number of circulating endothelial cells, in diabetes was not linked directly to glycemic control (HbA 1c [A1C]) (5). Extracellular matrix (ECM) interactions with endothelial cells maintain cell survival (6) and support angiogenesis driven by vascular endothelial-derived growth factor and other angiogenic factors (7). Early stages of microangiopathy and wound healing are characterized by development of acellular capillaries and decreased angiogenesis with consequent ischemia (8). A metabolic link to ECM disengagement of endothelial cells and impaired angiogenesis has not been identified.Most cell adhesion and signaling occur via integrins, which mediate a variety of cell-cell and cell-matrix interactions. The ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins recognize the GFOGER sequence found in collagens (9,10) (Fig. 1A). Several integrins recognize the RGD sequence within ECM proteins (6,11) where the RGD moiety binds astride the integrin ␣-and ␤-subunits with the Arg residue making electrostatic interaction with one or two Asp residues of the ␣-subunit (12,13).Methylglyoxal is a potent arginine-directed glycating agent formed mainly by the degradation of triosephosphates (14,15) with increased flux of formation in hyperglycemia associated with diabetes (16). It reacts with arginine residues to form a hydroimidazolone derivative, N␦-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)residues, an advanced glycation end product (AGE) (17,18), with loss of associated side chain positive charge (19) (Fig. 1B). MG-H1 residues are a major type of protein damage by glycation in diabetes, occurring on both cellular and extracellular proteins (20,21). Increased concentration of MG-H1 residues in plasma protein of diabetic patients was not linked directly to A1C (22), probably because methylglyoxal formation is increased in both fasting and postprandial hyperglycemia (16,23) and influenced by factors other than hyperglycemia (low glyceraldehyde-3-phosphate dehydrogenase activity [24]). MG-H1 residue formation occurred at susceptible hotspot sites in proteins with loss of functional activity (19). The surface sheath network of type IV collagen in blood vessels (25) binds integrins of vascular endothelial cells, anchoring and sustaining the vascular endothelium by interaction with integrins at GFOGER and RGD sites of the triple helical domain (9,26). These integrin binding sites are potential targets for methylglyoxal modification.We report here that modification by methylglyoxal of GFOGER and RGD sites in type IV collagen in hyperglycemia impairs ECM attachment, viability, and angiogenic activity of endothelial ce...

show abstract

Susceptibility to Diabetic Nephropathy Is Related to Dicarbonyl and Oxidative Stress

Cited by 168 publications

References 57 publications

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

Glyoxalase-1 overexpression reduces endothelial dysfunction and attenuates early renal impairment in a rat model of diabetes

Oxidative Stress-mediated Mesangial Cell Proliferation Requires RAC-1/Reactive Oxygen Species Production and β4 Integrin Expression

Increased Dicarbonyl Metabolism in Endothelial Cells in Hyperglycemia Induces Anoikis and Impairs Angiogenesis by RGD and GFOGER Motif Modification

Contact Info

Product

Resources

About