eNOS Knockout Mice with Advanced Diabetic Nephropathy Have Less Benefit from Renin-Angiotensin Blockade than from Aldosterone Receptor Antagonists

Kosugi, Tomoki; Heinig, Marcelo; Nakayama, Takahiro; Matsuo, Seiichi; Nakagawa, Takahiko

doi:10.2353/ajpath.2010.090578

Cited by 53 publications

(61 citation statements)

References 30 publications

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“…This could result from varied genetic background, altered methods of diabetic induction (46), or the presence of endothelial NOS deficiency (18). Also, we showed that in diabetic aortas, either the contraction or 6-keto-PGF 1␣ evoked by AA was similar to that of control nondiabetic mice; however, the level of COX-1 was lower in diabetic aortas and kidneys.…”

Section: Discussionmentioning

confidence: 68%

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Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Zhu

Liu

Luo

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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. Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in noninsulin-dependent diabetic mice induced by high-fat diet and streptozotocin. Am J Physiol Heart Circ Physiol 307: H319 -H327, 2014. First published May 30, 2014 doi:10.1152/ajpheart.00022.2014.-This study tested the hypothesis that in diabetic arteries, cyclooxygenase (COX)-1 mediates endothelial prostacyclin (PGI2) synthesis, which evokes vasoconstrictor activity under the pathological condition. Non-insulin-dependent diabetes was induced to C57BL/6 mice and those with COX-1 deficiency (COX-1 Ϫ/Ϫ mice) using a high-fat diet in combination with streptozotocin injection. In vitro analyses were performed 3 mo after. Results showed that in diabetic aortas, the endothelial muscarinic receptor agonist ACh evoked an endothelium-dependent production of the PGI2 metabolite 6-keto-PGF1␣, which was abolished in COX-1 Ϫ/Ϫ mice. Meanwhile, COX-1 deficiency or COX-1 inhibition prevented vasoconstrictor activity in diabetic abdominal aortas, resulting in enhanced relaxation evoked by ACh. In a similar manner, COX-1 deficiency increased the relaxation evoked by ACh in nitric oxide synthase-inhibited diabetic renal arteries. Also, in diabetic abdominal aortas and/or renal arteries, both PGI2 and the COX substrate arachidonic acid evoked contractions similar to those of nondiabetic mice. However, the contraction to arachidonic acid, but not that to PGI2, was abolished in vessels from COX-1 Ϫ/Ϫ mice. Moreover, we found that 3 mo after streptozotocin injection, systemic blood pressure increased in diabetic C57BL/6 mice but not in diabetic COX-1 Ϫ/Ϫ mice. These results explicitly demonstrate that in the given arteries from non-insulin-dependent diabetic mice, COX-1 remains a major contributor to the endothelial PGI2 synthesis that evokes vasoconstrictor activity under the pathological condition. Also, our data suggest that COX-1 deficiency prevents or attenuates diabetic hypertension in mice, although this could be related to the loss of COX-1-mediated activities derived from both vascular and nonvascular tissues. diabetes; arachidonic acid; metabolism; thromboxane prostanoid receptors; contraction CYCLOOXYGENASE (COX

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Section: Discussionmentioning

confidence: 68%

“…However, some previous reports have indicated that hypertension can develop 1 or 2 wk after diabetic induction (18,46). This could result from varied genetic background, altered methods of diabetic induction (46), or the presence of endothelial NOS deficiency (18).…”

Section: Discussionmentioning

confidence: 93%

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Zhu

Liu

Luo

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…In the case of the former, a number of RAAS components have been found to be upregulated with diabetes in the kidneys of eNOS 2/2 mice. 51 RAAS activation has also been described in the hearts of triply deficient n/i/eNOS 2/2 mice, although the mechanisms underlying this response have similarly not been defined. 52 In this study, we observed an approximate 50% increase in renal AngII with new-onset diabetes in wild-type mice and no change in eNOS 2/2 animals.…”

Section: Discussionmentioning

confidence: 99%

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

Yuen

Stead

Zhang

et al. 2012

Journal of the American Society of Nephrology

129

130

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Endothelial nitric oxide synthase (eNOS) deficiency may contribute to the pathogenesis of diabetic nephropathy in both experimental models and humans, but the underlying mechanism is not fully understood. Here, we studied two common sequelae of endothelial dysfunction in diabetes: glomerular capillary growth and effects on neighboring podocytes. Streptozotocin-induced diabetes increased glomerular capillary volume in both C57BL/6 and eNOS 2/2 mice. Inhibiting the vascular endothelial growth factor receptor attenuated albuminuria in diabetic C57BL/6 mice but not in diabetic eNOS 2/2 mice, even though it inhibited glomerular capillary enlargement in both. In eNOS 2/2 mice, an acute podocytopathy and heavy albuminuria occurred as early as 2 weeks after inducing diabetes, but treatment with either captopril or losartan prevented these effects. In vitro, serum derived from diabetic eNOS 2/2 mice augmented actin filament rearrangement in cultured podocytes. Furthermore, conditioned medium derived from eNOS 2/2 glomerular endothelial cells exposed to both high glucose and angiotensin II activated podocyte RhoA. Taken together, these results suggest that the combined effects of eNOS deficiency and hyperglycemia contribute to podocyte injury, highlighting the importance of communication between endothelial cells and podocytes in diabetes. Identifying mediators of this communication may lead to the future development of therapies targeting endothelial dysfunction in albuminuric individuals with diabetes.

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“…Accordingly, the aldosterone antagonist spironolactone reduces blood pressure and attenuates renal injury. 93 …”

Section: Disturbances Of No Availability In Early and Advanced Diabetmentioning

confidence: 99%

The Renal Endothelium in Diabetic Nephropathy

et al. 2013

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Diabetic nephropathy is the leading cause of end-stage renal disease. Diabetes mellitus is characterized by generalized endothelial dysfunction. However, recent data also emphasizes the role of local renal endothelium dysfunction in the pathogenesis of diabetic nephropathy. Hyperglycemia triggers a complex network of signal-transduction molecules, transcription factors, and mediators that culminate in endothelial dysfunction. In the glomerulus, vascular endothelial growth factor-A (VEGF)-induced neoangiogenesis may contribute to the initial hyperfiltration and microalbuminuria due to increased filtration area and immaturity of the neovessels, respectively. However, subsequent decrease in podocytes number decreases VEGF production resulting in capillary rarefaction and decreased glomerular filtration rate (GFR). Decreased nitric oxide availability also plays a significant role in the development of advanced lesions of diabetic nephropathy through disruption of glomerular autoregulation, uncontrolled VEGF action, release of prothrombotic substances by endothelial cells and angiotensin-II-independent aldosterone production. In addition, disturbances in endothelial glycocalyx contribute to decreased permselectivity and microalbuminuria; whereas there are recent evidences that reduced glomerular fenestral endothelium leads to decreased GFR levels. Endothelial repair mechanisms are also impaired in diabetes, since circulating endothelial progenitor cells number is decreased in diabetic patients with microalbuminuria. Finally, in the context of elevated profibrotic cytokine transforming growth factor-β levels, endothelial cells also confer to the deteriorating process of fibrosis in advanced diabetic nephropathy through endothelial to mesenchymal transition.

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eNOS Knockout Mice with Advanced Diabetic Nephropathy Have Less Benefit from Renin-Angiotensin Blockade than from Aldosterone Receptor Antagonists

Cited by 53 publications

References 30 publications

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

Vasoconstrictor role of cyclooxygenase-1-mediated prostacyclin synthesis in non-insulin-dependent diabetic mice induced by high-fat diet and streptozotocin

eNOS Deficiency Predisposes Podocytes to Injury in Diabetes

The Renal Endothelium in Diabetic Nephropathy

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