Proteasome-Dependent Degradation of Guanosine 5′-Triphosphate Cyclohydrolase I Causes Tetrahydrobiopterin Deficiency in Diabetes Mellitus

Xu, Jian; Wu, Yong; Song, Ping; Zhang, Miao; Wang, Shuangxi; Zou, Ming‐Hui

doi:10.1161/circulationaha.106.684795

Cited by 174 publications

(176 citation statements)

References 48 publications

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“…In addition, the resolution of GTPCH1, which is an enzyme involved in the production of BH4, is promoted by proteasome-dependent degradation under the presence of peroxynitrite. 27 Consequently, reduced production of BH4 may induce eNOS uncoupling.…”

Section: Discussionmentioning

confidence: 99%

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

et al. 2009

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Hypertensive vascular disorders are characterized by endothelial dysfunction. Loss of renal autoregulation causes glomerular hypertension. However, the relationship between the autoregulatory response and glomerular damage has not been well examined. We examined the contributions of uncoupled endothelial nitric oxide synthase (eNOS) in hypertensive renal disease, and the relationship between the degree of autoregulation impairment and glomerular injury. We also investigated the effects of telmisartan on eNOS coupling and renal autoregulation. Male Dahl salt-sensitive hypertensive (DS) rats (14-week old) fed an 8% salt diet were used to examine endothelial dysfunction and impaired renal autoregulation caused by glomerular hypertension. Some DS rats were treated with telmisartan (3.0 mg kg À1 day À1 ), an angiotensin receptor blocker, for 2 weeks. Increased superoxide production and decreased nitric oxide production, as detected by fluorescent indicator perfusion methods, were observed in the glomeruli and arterioles of hypertensive DS rats. Telmisartan improved the imbalance of superoxide and nitric oxide in the glomeruli and arterioles. Decreased serum tetrahydrobiopterin levels and coupled eNOS seen in the DS rat kidney were improved with telmisartan treatment. The endothelial relaxation reaction was impaired in DS rat aortic arteries. Autoregulatory capacity in response to step changes in perfusion pressure was also impaired in DS rat kidney. Treatment with telmisartan improved these abnormalities. Endothelial dysfunction in the glomeruli and impaired renal autoregulation, which may cause glomerular sclerosis, were observed in DS rat kidney. Telmisartan treatment improves these dysfunctions in hypertensive renal disease.

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Section: Discussionmentioning

confidence: 99%

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

et al. 2009

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“…22 Xu et al reported that proteasome-dependent degradation of GTPCH I was related to endothelial dysfunction in diabetes. 19 Wang et al reported that the inhibition of GTPCH I degradation by AMPK activation attenuated endothelial dysfunction. 23 Our data showed that metformin exerts a protective effect on GEnCs as well as vascular endothelial cells via maintenance of GTPCH I level.…”

Section: Discussionmentioning

confidence: 99%

“…HG activates 26S proteasome, resulting in enhanced degradation of GTPCH I in endothelial cells. 19 We evaluated 26S proteasome activity induced by high glucose stimulation and the effect of metformin. HG significantly increased 26S proteasome activity in human GEnCs.…”

Section: Evaluation Of Biopterin Levels and Enos Dimer/ Monomer Strucmentioning

confidence: 99%

“…18 In diabetes, GTPCH I degradation is accelerated in a proteasome-dependent manner. 19 Therefore, BH4 deficiency due to oxidation and acceleration of GTPCH I degradation is closely associated with nitric oxide synthase (NOS) dysfunction in diabetic vascular complications. However, the role of intrarenal GTPCH I and its molecular pathway in diabetic nephropathy have yet to be elucidated.…”

mentioning

confidence: 99%

“…22 Moreover, some reports show that proteasome-dependent GTPCH I degradation is key for diabetesinduced endothelial dysfunction. 19,23 Therefore, we also investigated whether metformin, an oral hypoglycemic agent and AMPK activator, exerts a protective effect in diabetic nephropathy.…”

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confidence: 99%

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Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy

Kidokoro

Satoh²,

Channon

et al. 2013

Journal of the American Society of Nephrology

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In diabetes, endothelial nitric oxide synthase (eNOS) produces superoxide anion rather than nitric oxide, referred to as "eNOS uncoupling," which may contribute to endothelial dysfunction, albuminuria, and diabetic nephropathy. Reduced levels of endothelium-derived tetrahydrobiopterin (BH4), an essential cofactor for eNOS, promote eNOS uncoupling. Accelerated degradation of guanosine triphosphate cyclohydrolase I (GTPCH I), the rate-limiting enzyme in BH4 biosynthesis, also occurs in diabetes, suggesting that GTPCH I may have a role in diabetic microvascular disease. Here, we crossed endothelium-dominant GTPCH I transgenic mice with Ins2 +/Akita diabetic mice and found that endothelial overexpression of GTPCH I led to higher levels of intrarenal BH4 and lower levels of urinary albumin and reactive oxygen species compared with diabetic control mice. Furthermore, GTPCH I overexpression attenuated the hyperpermeability of macromolecules observed in diabetic control mice. In addition, we treated Ins2 +/Akita mice with metformin, which activates AMP-activated protein kinase (AMPK) and thereby slows the degradation of GTPCH I; despite blood glucose levels that were similar to untreated mice, those treated with metformin had significantly less albuminuria. Similarly, in vitro, treating human glomerular endothelial cells with AMPK activators attenuated glucose-induced reductions in phospho-AMPK, GTPCH I, and coupled eNOS. Taken together, these data suggest that maintenance of endothelial GTPCH I expression and the resulting improvement in BH4 biosynthesis ameliorate diabetic nephropathy.

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Protein Oxidation in Some Age‐Related Diseases

2012

Protein Oxidation and Aging

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Proteasome-Dependent Degradation of Guanosine 5′-Triphosphate Cyclohydrolase I Causes Tetrahydrobiopterin Deficiency in Diabetes Mellitus

Cited by 174 publications

References 48 publications

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

Telmisartan improves endothelial dysfunction and renal autoregulation in Dahl salt-sensitive rats

Maintenance of Endothelial Guanosine Triphosphate Cyclohydrolase I Ameliorates Diabetic Nephropathy

Protein Oxidation in Some Age‐Related Diseases

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