Differences in susceptibility to diabetic nephropathy (DN) between mouse strains with identical levels of hyperglycemia correlate with renal levels of oxidative stress, shown previously to play a central role in the pathogenesis of DN. Susceptibility to DN appears to be genetically determined, but the critical genes have not yet been identified. Overexpression of the enzyme glyoxalase 1 (Glo1), which prevents posttranslational modification of proteins by the glycolysis-derived α-oxoaldehyde, methylglyoxal (MG), prevents hyperglycemia-induced oxidative stress in cultured cells and model organisms. In this study, we show that in nondiabetic mice, knockdown of Glo1 increases to diabetic levels both MG modification of glomerular proteins and oxidative stress, causing alterations in kidney morphology indistinguishable from those caused by diabetes. We also show that in diabetic mice, Glo1 overexpression completely prevents diabetes-induced increases in MG modification of glomerular proteins, increased oxidative stress, and the development of diabetic kidney pathology, despite unchanged levels of diabetic hyperglycemia. Together, these data indicate that Glo1 activity regulates the sensitivity of the kidney to hyperglycemic-induced renal pathology and that alterations in the rate of MG detoxification are sufficient to determine the glycemic set point at which DN occurs.
Glucagon-like peptide-1 (GLP-1) is an endogenous intestinal peptide that enhances glucose-stimulated insulin secretion. Its natural cleavage product GLP-1 (9-36)amide possesses distinct properties and does not affect insulin secretion. Here we report that pretreatment of hippocampal slices with GLP-1(9-36)amide prevented impaired long-term potentiation (LTP) and enhanced long-term depression (LTD) induced by exogenous amyloid β peptide (Aβ1-42). Similarly, hippocampal LTP impairments in APP/PS1 mutant mice that model Alzheimer’s disease (AD) were prevented by GLP-1(9-36)amide. In addition, treatment of APP/PS1 mice with GLP-1 (9-36)amide at an age where they display impaired spatial and contextual fear memory resulted in a reversal of their memory defects. At the molecular level, GLP-1 (9-36)amide reduced elevated levels of mitochondrial-derived reactive oxygen species (ROS) and restored dysregulated Akt-GSK3β signaling in the hippocampus of APP/PS1 mice. Our findings suggest that GLP-1(9-36)amide treatment may have therapeutic potential for AD and other diseases associated with cognitive dysfunction.
In response to blood vessel injury, hemostasis is initiated by platelet activation, advanced by thrombin generation, and tempered by fibrinolysis. The primary fibrinolytic protease, plasmin, can be activated either on a fibrin-containing thrombus or on cells. Annexin A2 (A2) heterotetramer (A2⅐p11) 2 is a key profibrinolytic complex that assembles plasminogen and tissue plasminogen activator and promotes plasmin generation. We now report that, in endothelial cells, plasmin specifically induces activation of conventional PKC, which phosphorylates serine 11 and serine 25 of A2, triggering dissociation of the (A2⅐p11) 2 tetramer. The resulting free p11 undergoes ubiquitinmediated proteasomal degradation, thus preventing further translocation of A2 to the cell surface. In vivo, pretreatment of A2 ؉/؉ but not A2 ؊/؊ mice with a conventional PKC inhibitor significantly reduced thrombosis in a carotid artery injury model. These results indicate that augmentation of fibrinolytic vascular surveillance by blockade of serine phosphorylation is A2-dependent. We also demonstrate that plasmin-induced phosphorylation of A2 requires both cleavage of A2 and activation of Toll-like receptor 4 on the cell surface. We propose that plasmin can limit its own generation by triggering a finely tuned "feedback" mechanism whereby A2 becomes serine-phosphorylated, dissociates from p11, and fails to translocate to the cell surface.The human hemostatic system represents a coordinated balance between procoagulant and anticoagulant/profibrinolytic activities. Together, these systems prevent blood loss while maintaining blood flow. Plasmin, the major protease of the fibrinolytic system, acts to digest insoluble fibrin into soluble fibrin degradation products. Plasmin generation is modulated by plasminogen activators and plasminogen activator inhibitors and is further regulated by binding of plasminogen and its activators to cell surface receptors (1). Membrane-associated annexin A2 (A2) 3 is part of a heterotetrameric complex in which the N termini of two copies of A2 bind to two copies of the S100 family protein, S100A10 (p11) (2). A2, a member of the annexin superfamily, consists of a highly conserved C-terminal phospholipid-binding core domain and an N-terminal ligandinteracting domain (3). Complex formation with p11 increases the affinity of A2 for calcium and phospholipids, thereby directing it to cellular membranes (4). Components of the (A2⅐p11) 2 tetramer, moreover, specifically bind tissue plasminogen activator (t-PA) and plasminogen and strongly enhance plasmin generation (5-8, 52).Several lines of evidence identify the (A2⅐p11) 2 complex as a significant regulator of fibrin balance in vivo. First, A2 Ϫ/Ϫ microvascular endothelial cells lack t-PA cofactor activity, and the fibrin content of highly perfused A2 Ϫ/Ϫ tissues is ϳ2-fold greater than that observed in wild type controls (9). In addition, arterial injury in A2 Ϫ/Ϫ mice is followed by a 2-fold increase in thrombotic vascular occlusion with an equivalent reduction in blood flo...
Oxygen-induced retinopathy (OIR) is a well-characterized model for retinopathy of prematurity, a disorder that results from rapid microvascular proliferation after exposure of the retina to high oxygen levels. Here, we report that the proliferative phase of OIR requires transcriptional induction of the annexin A2 (A2) gene through the direct action of the hypoxiainducible factor-1 complex. We show, in addition, that A2 stabilizes its binding partner, p11, and promotes OIR-related angiogenesis by enabling clearance of perivascular fibrin. Adenoviral-mediated restoration of A2 expression restores neovascularization in the oxygen-primed Anxa2 ؊/؊ retina and reinstates plasmin generation and directed migration in cultured Anxa2 ؊/؊ endothelial cells. Systemic depletion of fibrin repairs the neovascular response to high oxygen treatment in the Anxa2 ؊/؊ retina, whereas inhibition of plasminogen activation dampens angiogenesis under the same conditions. These findings show that the A2 system enables retinal neoangiogenesis in OIR by enhancing perivascular activation of plasmin and remodeling of fibrin. These data suggest new potential approaches to retinal angiogenic disorders on the basis of modulation of perivascular fibrinolysis. (Blood. 2011;118(10): 2918-2929) IntroductionRetinopathy of prematurity (ROP) is the main cause of severe visual impairment in children in the developed world. 1 A vascular proliferative disorder that affects preterm and low-birth weight infants on exposure to supraphysiologic oxygen tension, ROP is increasing in incidence with the greater availability of neonatal intensive care, and more frequent survival of very-low-birth weight infants. In the initial, vaso-obliterative phase of ROP, high oxygen exposure provokes endothelial cell death because of oxidative injury, nitrative stress, and suppression of oxygen-related growth factors. 2 In the second phase, the resulting retinal ischemia leads to neovascularization characterized by excessive proliferation and vitreal invasion of blood vessels. This pathologic response arises when neurons and supporting astrocytes become severely metabolically deprived because of vaso-obliteration and produce exaggerated amounts of oxygen-regulated angiogenic factors, such as VEGF and erythropoietin. These agents stimulate the regrowth of abnormal vessels that proliferate toward the vitreous, can form a fibrous scar, and, on contraction, can apply tractional forces that ultimately may detach the retina from its underlying pigment epithelium. Scarring and retinal detachment can lead to vision loss and blindness. Current preventive measures for ROP include restriction of tissue oxygenation and the use of antioxidants, whereas standard treatment for established disease requires ablative laser photocoagulation or cryotherapy. Newer therapies with VEGF-neutralizing antibodies appear promising, but their effects on retinal ganglion cell integrity, the developing cerebral vasculature, and long-term visual acuity and visual fields are unknown. 2 Annexin A2 is a cell...
The reactive dicarbonyls, glyoxal and methylglyoxal (MG), increase in diabetes and may participate in the development of diabetic complications. Glyoxal and MG are detoxified by the sequential activities of glyoxalase 1 (GLO1) and glyoxalase 2. To determine the contribution of these dicarbonyls to the etiology of complications, we have genetically manipulated GLO1 levels in apolipoprotein E‐null (Apoe−/−) mice. Male Apoe−/− mice, hemizygous for a human GLO1 transgene (GLO1TGApoe−/− mice) or male nontransgenic Apoe−/− litter mates were injected with streptozotocin or vehicle and 6 or 20 weeks later, aortic atherosclerosis was quantified. The GLO1 transgene lessened streptozotocin (STZ)‐induced increases in immunoreactive hydroimidazolone (MG‐H1). Compared to nondiabetic mice, STZ‐treated GLO1TGApoe−/− and Apoe−/− mice had increased serum cholesterol and triglycerides and increased atherosclerosis at both times after diabetes induction. While the increased GLO1 activity in the GLO1TGApoe−/− mice failed to protect against diabetic atherosclerosis, it lessened glomerular mesangial expansion, prevented albuminuria and lowered renal levels of dicarbonyls and protein glycation adducts. Aortic atherosclerosis was also quantified in 22‐week‐old, male normoglycemic Glo1 knockdown mice on an Apoe−/− background (Glo1KDApoe−/− mice), an age at which Glo1KD mice exhibit albuminuria and renal pathology similar to that of diabetic mice. In spite of ~75% decrease in GLO1 activity and increased aortic MG‐H1, the Glo1KDApoe−/− mice did not show increased atherosclerosis compared to age‐matched Apoe−/− mice. Thus, manipulation of GLO1 activity does not affect the development of early aortic atherosclerosis in Apoe−/− mice but can dictate the onset of kidney disease independently of blood glucose levels.
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