Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy

Satoh, Minoru; Fujimoto, Sohachi; Arakawa, Sayaka; Yada, Toyotaka; Namikoshi, Tamehachi; Haruna, Yoshisuke; Horike, Hideyuki; Sasaki, Tatsuya; Kashihara, Naoki

doi:10.1093/ndt/gfn357

Cited by 102 publications

(74 citation statements)

References 31 publications

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“…12 Primers and probes for TaqMan analysis were designed with Primer 3 online software (http:// frodo.wi.mit.edu/primer3/; accessed 1 January 2010) based on sequence information from GenBank. Primers and probes are listed in Supplementary Figure 2.…”

Section: Quantitative Rt-pcr Of Mitochondrial Mrna Expressionmentioning

confidence: 99%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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Decreased expression of vascular endothelial growth factor (VEGF) in the renal tubules is thought to cause progressive loss of the renal microvasculature with age. Mitochondrial dysfunction may be a principal phenomenon underlying the process of aging. The relation between VEGF expression and mitochondrial dysfunction in aging is not fully understood. We hypothesized that mitochondrial dysfunction blocks VEGF expression and contributes to impaired angiogenesis in the aging kidney. The aim of this study was to assess the role of mitochondria in VEGF expression in the aging rat kidney. We evaluated the accumulation of 8-hydroxy-2 0 -deoxyguanosine in mitochondrial DNA, as well as mitochondrial dysfunction, as assessed by electron microscopy of mitochondrial structure and histochemical staining for respiratory chain complex IV, in aging rat kidney. An increase in hypoxic area and a decrease in peritubular capillaries were detected in the cortex of aging rat kidneys; however, upregulation of VEGF expression was not observed. The expression of VEGF in proximal tubular epithelial cells in response to hypoxia was suppressed by the mitochondrial electron transfer inhibitor myxothiazol. Mitochondrial DNA-deficient cells also failed to upregulate VEGF expression under hypoxic conditions. These results indicate that impairment of VEGF upregulation, possibly as a result of mitochondrial dysfunction, contributes to impaired angiogenesis, which in turn leads to renal injury in the aging rat kidney.

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Section: Quantitative Rt-pcr Of Mitochondrial Mrna Expressionmentioning

confidence: 99%

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Satoh

Fujimoto

Horike

et al. 2011

Laboratory Investigation

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“…RNA isolation and real-time quantitative PCR for GTPCH1 and P2rx1 were performed using the ABI Prism 7700 sequence detection system (Applied Biosystems, Foster City, CA, USA), as described previously. 19 Primers and probes for P2rx1 (NM_012997) were as follows: rat P2rx1 forward primer: 5¢-CGTCATTGGGTGGGTGTT-3¢; reverse primer: 5¢-AGCTGGGTCA CAGCCAAG-3¢; TaqMan probe: 5¢-FAM-TCAGCAGTGTGTCCGTGAAGCT CA-TAMRA-3¢. Fold-change analysis was based on standardizing RNA levels by normalizing to glyceraldehyde-3-phosphate dehydrogenase levels in the sample.…”

Section: Real-time Quantitative Pcrmentioning

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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“…eNOS is expressed in MCs, and its uncoupling has been linked to the decline in NO levels observed in the diabetic environment (34 -36). A role of Ang II in eNOS uncoupling and the decrease in renal NO production is suggested by the observations that angiotensin II type 1 receptor blockade restores eNOS function and NO levels in experimental models of diabetes (37,38). However, the molecular mechanisms by which eNOS function and NO bioavailability are altered by Ang II in renal cells are unknown.…”

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confidence: 99%

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

Lee¹,

Wauquier²,

Eid³

et al. 2013

Journal of Biological Chemistry

114

105

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Background: Oxidative stress is critical for the fibrotic response of mesangial cells (MCs) to angiotensin II. Results: Nox4-and mitochondrial reactive oxygen species (ROS)-dependent endothelial nitric-oxide synthase (eNOS) uncoupling led to fibronectin accumulation in MCs stimulated by angiotensin II. Conclusion: The Nox4/mitochondrial ROS/eNOS pathway mediates angiotensin II-induced MC injury. Significance: Targeting Nox4 and mitochondrial ROS is a promising therapeutic approach.

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Angiotensin II type 1 receptor blocker ameliorates uncoupled endothelial nitric oxide synthase in rats with experimental diabetic nephropathy

Cited by 102 publications

References 31 publications

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

Mitochondrial damage-induced impairment of angiogenesis in the aging rat kidney

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

Nox4 NADPH Oxidase Mediates Peroxynitrite-dependent Uncoupling of Endothelial Nitric-oxide Synthase and Fibronectin Expression in Response to Angiotensin II

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