Jak2/Stat1 pathway mediated tetrahydrobiopterin up-regulation contributes to nitric oxide overproduction in high-glucose cultured rat mesangial cells

2015 ◽  
Vol 93 (1) ◽  
pp. 81-89 ◽  
Author(s):  
Jian-Yun Wang ◽  
Shuai Liu ◽  
Na Qin ◽  
Qian-Qian Yang ◽  
Hao Guo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
High Glucose ◽  
Mesangial Cells ◽  
Oxygen Species ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Related Factors ◽  
Oxide Synthase ◽  
Rate Limiting ◽  
Early Diabetic Nephropathy

Nitric oxide (NO) is crucial for the progression of early diabetic nephropathy (DN). It is important to clarify the mechanism for the production of NO in mesangial cells (MCs). In this study, the amounts/activities of related factors such as reactive oxygen species (ROS), NO, 3 isoforms of nitric oxide synthase (NOS), tetrahydrobiopterin (BH4), GTP cyclohydrolase I (GTPCH I), Jak2, and Stat1 were determined using high-glucose cultured rat MCs. The results showed that the production of BH4 under oxidative stress was strongly stimulated by its rate-limiting enzyme GTP cyclohydrolase, which increased the expression and activity of inducible NOS to facilitate NO synthesis. Furthermore, the relative quantities of activated-Jak2 and activated-Stat1 were increased. Therefore, Jak2/Stat1 pathway mediated BH4 up-regulation can contribute to excessive NO in high-glucose cultured MCs. Our results will be helpful for screening new targets to improve the therapy for early DN.

Endothelin-1 Inhibits Induction of Nitric Oxide Synthase and GTP Cyclohydrolase I in Rat Mesangial Cells

Pharmacology ◽  
1996 ◽  
Vol 53 (4) ◽  
pp. 241-249 ◽  
Author(s):  
Junichi Hirahashi ◽  
Toshio Nakaki ◽  
Keiichi Hishikawa ◽  
Takeshi Marumo ◽  
Toshio Yasumori ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Mesangial Cells ◽  
Gtp Cyclohydrolase I ◽  
Gtp Cyclohydrolase ◽  
Endothelin 1 ◽  
Oxide Synthase

Tetrahydrobiopterin reverses the inhibition of nitric oxide by high glucose in cultured murine mesangial cells

2001 ◽  
Vol 281 (1) ◽  
pp. F179-F188 ◽  
Author(s):  
Sharma S. Prabhakar
Keyword(s):  
Nitric Oxide ◽  
High Glucose ◽  
Mesangial Cells ◽  
Inos Activity ◽  
Gene And Protein Expression ◽  
Matrix Production ◽  
The Stability ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

Alterations of intrarenal nitric oxide (NO) synthesis play an important role in the pathogenesis and progression of diabetic nephropathy. We tested the hypothesis that hyperglycemia modulates intrarenal NO synthesis, which might mediate the mesangial cell proliferation and matrix production. Murine mesangial cells were grown in media containing varying glucose concentrations, and cytokine-induced NO synthesis was assayed by chemiluminescence using an NO analyzer. High media glucose (25 mM) inhibited NO synthesis in a time-dependent fashion. This inhibition was posttranslational as revealed by analysis of inducible nitric oxide synthase (iNOS) gene and protein expression. l-Arginine supplementation partially reversed the inhibition whereas addition of tetrahydrobiopterin (BH4), a cofactor for NOS, restored the inducibility of NO synthesis. The in vitro [3H]citrulline assay for iNOS activity indicated that high glucose decreased BH4 availability whereas examination of the BH4synthetic pathway suggested decreased BH4 stability rather than synthesis, a defect that was corrected by ascorbic acid. We conclude that hyperglycemia inhibits NO synthesis in mesangial cells by a posttranslational defect that might involve the stability and hence availability of BH4.

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