Impaired Endothelium-Dependent Vascular Responses of Retinal and Intrarenal Arteries in Patients With Type 2 Diabetes

Kawagishi, Takahiko; Matsuyoshi, Miyoko; Emoto, Masanori; Taniwaki, Hiromichi; Kanda, Hiroyuki; Okuno, Yasuhisa; Inaba, Masaaki; Ishimura, Eiji; Nishizawà, Yoshiki; Morii, Hirotoshi

doi:10.1161/01.atv.19.10.2509

Cited by 44 publications

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“…We also reported that the DD genotype of ACE genes was associated with increased RI in type 1 diabetes (21). We have reported that endotheliumdependent vascular responses of the retinal and intrarenal arteries were impaired in type 2 diabetic patients with early nephropathy (22).…”

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confidence: 84%

Relations Between ACE Gene and ecNOS Gene Polymorphisms and Resistive Index in Type 2 Diabetic Patients With Nephropathy

et al. 2001

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OBJECTIVE -ACE and endothelial cell nitric oxide synthase (ecNOS) genotypes have been reported to be related to the incidence of renal diseases and coronary artery diseases. In order to assess the effect of the gene polymorphism of both ACE and ecNOS on renal hemodynamic abnormality, we examined 155 Japanese patients with type 2 diabetes with various stages of nephropathy.RESEARCH DESIGN AND METHODS -The patients ranged in age from 40 to 72 years (92 men and 63 women). They were divided into four groups: group 1 consisted of patients with urinary albumin excretion (UAE) Ͻ30 mg/day (n ϭ 69), group 2 had 30 Յ UAE Ͻ 300 mg/day (n ϭ 44), group 3 had UAE Ն300 mg/day and serum creatinine Ͻ1.5 mg/dl (n ϭ 22), and group 4 had serum creatinine Ͼ1.5 mg/dl (n ϭ 20). Intrarenal hemodynamics were studied by duplex Doppler sonography in patients with type 2 diabetes. The ACE and ecNOS gene polymorphisms were examined by polymerase chain reaction.RESULTS -There were no significant differences in sex, BMI, and blood glucose level, but there were differences in HbA 1c and lipoprotein profiles among the four groups. There were no significant differences in the distribution of ACE genotype or in the frequency of the ecNOS 4a allele among the four groups. Resistive index (RI) values of the interlobar arteries of group 4 were significantly higher than those of groups 1, 2, and 3, whereas the RI values were not significantly different among groups 1, 2, and 3. Multiple regression analysis showed that age, duration of diabetes, systolic and diastolic blood pressure, and creatinine clearance were significantly associated with the increased RI values, but that there was no significant association between RI values and the ecNOS genotype (R 2 ϭ 0.613, P Ͻ 0.0001).CONCLUSIONS -These results suggest that intrarenal hemodynamic abnormalities are present as a feature of the progression of nephropathy in type 2 diabetes, and that they are associated with age, duration of diabetes, decreased creatinine clearance, and blood pressure, but not with the genetic factors of the ACE and ecNOS gene polymorphism in nephropathy of type 2 diabetes. Diabetes Care 24:1653-1660, 2001S everal studies have demonstrated that diabetic nephropathy occurs in familial clusters, suggesting that a genetic factor(s) may be involved (1).ACE insertion/deletion (I/D) polymorphism of intron 16 was reported to be a genetic marker for coronary artery disease in the general population (2). Accordingly, the I/D polymorphism has been investigated as a strong candidate marker for genetic predisposition to diabetic vascular complications (3,4). However, studies of the association of the ACE genotype with diabetic complications, such as nephropathy, have yielded conflicting results (5-7).It is now established that endothelialderived nitric oxide (NO) plays a major role in vascular regulation in normal and disease states (8). NO is synthesized by endothelial cell NO synthase (ecNOS) in the vascular endothelium, and it plays a key role in the regulation of blood flow and pressure....

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Relations Between ACE Gene and ecNOS Gene Polymorphisms and Resistive Index in Type 2 Diabetic Patients With Nephropathy

et al. 2001

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“…Provided this is the case as on the platelet surface, the lower numbers of collagen receptors may be associated with the loose integrity and dysfunction of the endothelium, which is now regarded as one of the initial events that lead to progression of atherosclerosis (13). There is evidence that endothelium-dependent vasodilatation, one of the markers of endothelial functions, is impaired in patients with diabetes (32)(33)(34). Thus, endothelial dysfunction present in patients with diabetes may facilitate the contribution of the ␣2 integrin genotype on progression of atherosclerosis.…”

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The 807T Allele in α2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes

et al. 2002

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Polymorphism of ␣2 integrin (C807T) is shown to be associated with an increased incidence of thrombotic cardiovascular events. However, it is not clear whether this polymorphism is associated with atherosclerotic arterial wall thickening. In this study, we examined the association of C807T polymorphism with arterial wall thickness in 265 control subjects and 272 patients with type 2 diabetes. In all subjects, intima-media thickness of the right carotid artery in the 807TT group (0.649 ؎ 0.028 mm [SE]) was significantly (P ‫؍‬ 0.0228, Scheffe's F test) less than in the 807CC group (0.767 ؎ 0.033). This effect of polymorphism is gene dose dependent (P ‫؍‬ 0.0227, ANOVA). The similar association was also observed in patients with diabetes but not in control subjects. Multiple regression analysis in all subjects revealed that the T allele was inversely (␤ ‫؍‬ ؊0.095, P ‫؍‬ 0.021) associated with intima-media thickness independent of age, HbA 1c , and HDL cholesterol. Finally, an inverse relation between the occurrence of carotid plaque and the T allele was observed in patients with diabetes with an adjusted odds ratio of 0.487 (P ‫؍‬ 0.031) in multiple logistic regression analyses. These results suggest that the number of 807T alleles in ␣2 integrin is protective against atherosclerotic arterial wall thickening and the occurrence of plaque in patients with type 2 diabetes. Diabetes 51:1523-1528, 2002 P rogression of atherosclerosis is known to be related to vascular risk factors such as hypertension, smoking, diabetes, and high cholesterol levels. In addition to these conventional risk factors, genetic predispositions may enhance the risk of cardiovascular events (reviewed in Murata et al. [1]). Initially reported was the relation between a polymorphism of ACE and coronary arterial diseases (2). Other possible genetic risk factors include angiotensin II type I receptor, endothelial nitric oxide synthase, apolipoprotein E, lipoprotein lipase, paraoxonase, methylenetetrahydrofolate reductase, fibrinogen, plasminogen activator inhibitor-1, thrombomodulin, and platelet glycoproteins (GPs; see review [1]).The platelet membrane ␣2␤1 integrin, also known as GP Ia-IIa, serves as a platelet receptor for collagen (3). It mediates platelet primary adhesion to subendothelial tissues and activation (4,5). The gene encoding ␣2 integrin has at least eight polymorphisms, including two silent polymorphisms located within the intron (6). C807T (224Phe) and G873A (246Thr) were reported to be in linkage and associated with the expression density of GP Ia-IIa on the platelet surface (7). T807/A873 is associated with a higher expression of the receptor, and C807/G873 is associated with a lower expression density. The expression density of ␣2 integrin was also shown to be associated with the rate of platelet attachment to type I collagen, even under high shear rates (8).␣2␤1 integrin is also expressed in vascular endothelium (9 -11). In endothelial cells, ␣2␤1 integrin seems to function as a receptor for laminin as well as collagen (12), ...

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“…[2][3][4] Progressive and irreversible microvascular damage and loss are observed in the diabetic kidney, and a decrease in the function and density of intrarenal microvessels has been reported in several studies. [5][6][7][8] Furthermore, progressive podocyte injury, characterized by low microvessel density and number, hypertrophy, and foot process effacement, plays a central role in the development of DN in both type 1 and type 2 diabetes. 4,[9][10][11] Despite the crucial importance of the kidney, both as therapeutic target and as determinant of the prognosis of patients with DN, little is known about the mechanisms underlying kidney damage associated with diabetes.…”

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confidence: 99%

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

et al. 2015

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filtration barrier; MAP1LC3A/B/LC3A/B), microtubule-associated protein 1 light chain 3 a/b; MTOR, mechanistic target of rapamycin; Nphs2, nephrosis 2, podocin; SQSTM1, sequestosome 1; STZ, streptozotocin; TEM, transmission electron microscopy; TUBA, tubulin; a, WT1, Wilms tumor 1.The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelialspecific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.

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Impaired Endothelium-Dependent Vascular Responses of Retinal and Intrarenal Arteries in Patients With Type 2 Diabetes

Cited by 44 publications

References 40 publications

Relations Between ACE Gene and ecNOS Gene Polymorphisms and Resistive Index in Type 2 Diabetic Patients With Nephropathy

Relations Between ACE Gene and ecNOS Gene Polymorphisms and Resistive Index in Type 2 Diabetic Patients With Nephropathy

The 807T Allele in α2 Integrin Is Protective Against Atherosclerotic Arterial Wall Thickening and the Occurrence of Plaque in Patients With Type 2 Diabetes

Endothelial cell and podocyte autophagy synergistically protect from diabetes-induced glomerulosclerosis

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