Targeting of Rho Kinase Ameliorates Impairment of Diabetic Endothelial Function in Intrarenal Artery

Yin, Hongping; Hailong, Ru; Yu, Liping; Kang, Yanhua; Lin, Guohua; Chuanfei, Liu; Sun, Lixian; Shi, Liyun; Sun, Qinghua; Liu, Cui-Qing

doi:10.3390/ijms141020282

Cited by 8 publications

(9 citation statements)

References 39 publications

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“…In this line, increased ROK‐I expression and a rise in basal MYPT‐T853 phosphorylation were reported in a model of STZ‐induced diabetes (Yin et al. ). Supporting all aforementioned observations, our study also reports an elevation of basal phosphorylation of T853 in STZ diabetes.…”

Section: Discussionmentioning

confidence: 68%

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Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1

et al. 2019

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Diabetes mellitus (DM) is a metabolic disorder with high prevalence, and a major risk factor for macro‐ and microvascular abnormalities. This study was undertaken to explore the mechanisms of hypercontractility of murine femoral arteries (FA) obtained from mice with streptozotocin (STZ)‐induced diabetes and its relation to the phosphorylation profile of the myosin phosphatase target subunit 1, MYPT1. The immunoreactivity of MYPT1 toward phospho‐MYPT1‐T696, MYPT1‐T853, or MYPT1‐S695, used as a read out for MYPT1 phosphorylation, has been studied by Western Blotting. Contractile activity of FA from control and STZ mice has been studied by wire myography. At basal conditions (no treatment), the immunoreactivity of MYPT1‐T696/T853 was ~2‐fold higher in the STZ arteries compared with controls. No changes in MYPT1‐T696/853 phosphorylation were observed after stimulation with the Thromboxan‐A2 analog, U46619. Neither basal nor U46619‐stimulated phosphorylation of MYPT1 at S695 was affected by STZ treatment. Mechanical distensibility and basal tone of FA obtained from STZ animals were similar to controls. Maximal force after treatment of FA with the contractile agonists phenylephrine (10 μmol/L) or U46619 (1 μmol/L) was augmented in the arteries of STZ mice by ~2‐ and ~1.5‐fold, respectively. In summary, our study suggests that development of a hypercontractile phenotype in murine FA in STZ diabetes is at least partially related to an increase in phosphorylation of MLCP at MYPT1‐T696/853. Interestingly, the phosphorylation at S695 site was not altered in STZ‐induced diabetes, supporting the view that S695 may serve as a sensor for mechanical activity which is not directly involved in tone regulation.

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Section: Discussionmentioning

confidence: 68%

“…; Yin et al. ). At least part of this impairment and hypercontractile response were related to a reduction in eNOS dimer formation (Molnar et al.…”

Section: Introductionmentioning

confidence: 98%

Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1

et al. 2019

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“…On the same line, diabetesinduced endothelial aortic dysfunction is improved in ROCK knockout mice [232]. ROCK inhibitors such as Y-27632 and fasudil have shown promising therapeutic advantages on cardiovascular diseases including atherosclerosis, pulmonary and systemic hypertension and chronic heart failure [233,234], as well as significant beneficial effects on diabetic endothelial dysfunction of retinal [235], coronary [236] and intrarenal arteries [237]. In addition, fasudil has been able to limit TNF-alphamediated ICAM-1 expression and eNOS dephosphorylation in diabetic microvasculature [238].…”

Section: Rock (Rho-associated Kinase) Inhibitors -mentioning

confidence: 80%

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Potenza

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Salvia

et al. 2017

Pharmacological Research

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Abstract:The association of obesity and diabetes, termed "diabesity", defines a combination of primarily metabolic disorders with insulin resistance as the underlying common pathophysiology. Cardiovascular disorders associated with diabesity represent the leading cause of morbidity and mortality in the Western world. This makes diabesity, with its rising impacts on both health and economics, one of the most challenging biomedical and social threats of present century. The emerging comprehension of the genes whose alteration confers inter-individual differences on risk factors for diabetes or obesity, together with the potential role of genetically determined variants on mechanisms controlling responsiveness, effectiveness and safety of anti-diabetic therapy underlines the need of additional knowledge on molecular mechanisms involved in the pathophysiology of diabesity. Endothelial cell dysfunction, resulting from the unbalanced production of endothelialderived vascular mediators, is known to be present at the earliest stages of insulin resistance and obesity, and may precede the clinical diagnosis of diabetes by several years. Once considered as a mere consequence of metabolic abnormalities, it is now clear that endothelial dysfunctional activity may play a pivotal role in the progression of diabesity. In the vicious circle where vascular defects and metabolic disturbances worsen and reinforce each other, a low-grade, chronic, and 'cold' inflammation (metaflammation) has been suggested to serve as the pathophysiological link that binds endothelial and metabolic dysfunctions. In this paradigm, it is important to consider how traditional antidiabetic treatments (specifically addressing metabolic dysregulation) may directly impact on inflammatory processes or cardiovascular function. Indeed, not all drugs currently available to treat diabetes possess the same anti-inflammatory potential, or target endothelial cell function equally. Perspective strategies pointing at reducing metaflammation or directly addressing endothelial dysfunction may disclose beneficial consequences on metabolic regulation. This review focuses on existing and potential new approaches ameliorating endothelial dysfunction and vascular inflammation in the context of diabesity.

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“…Rho GTPases play an important role in renal integrity and function [ 29 , 39 , 40 ]. Of importance, transgenic mice expressing doxycycline-inducible constitutively active or dominant-negative RhoA in podocytes revealed that RhoA, in basal conditions, maintains the integrity of the glomerular filtration barrier, but increased RhoA activity promotes podocyte injury [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Of importance, transgenic mice expressing doxycycline-inducible constitutively active or dominant-negative RhoA in podocytes revealed that RhoA, in basal conditions, maintains the integrity of the glomerular filtration barrier, but increased RhoA activity promotes podocyte injury [ 39 ]. In addition, mice subjected to nephrectomy present podocyte dysfunction, which is attenuated by RhoA signaling inhibition [ 40 ]. RhoA also is involved in renal integrity in diabetic mice; its inhibitors attenuate diabetes-induced renal hypertrophy in different models of diabetes, including db/db mice [ 8 , 41 ], supporting a role for RhoA/Rho kinase in diabetes-associated nephropathy.…”

Section: Discussionmentioning

confidence: 99%

Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3

et al. 2016

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Potential benefits of statins in the treatment of chronic kidney disease beyond lipid-lowering effects have been described. However, molecular mechanisms involved in renoprotective actions of statins have not been fully elucidated. We questioned whether statins influence development of diabetic nephropathy through reactive oxygen species, RhoA and Akt/GSK3 pathway, known to be important in renal pathology. Diabetic mice (db/db) and their control counterparts (db/+) were treated with atorvastatin (10 mg/Kg/day, p.o., for 2 weeks). Diabetes-associated renal injury was characterized by albuminuria (albumin:creatinine ratio, db/+: 3.2 ± 0.6 vs. db/db: 12.5 ± 3.1*; *P<0.05), increased glomerular/mesangial surface area, and kidney hypertrophy. Renal injury was attenuated in atorvastatin-treated db/db mice. Increased ROS generation in the renal cortex of db/db mice was also inhibited by atorvastatin. ERK1/2 phosphorylation was increased in the renal cortex of db/db mice. Increased renal expression of Nox4 and proliferating cell nuclear antigen, observed in db/db mice, were abrogated by statin treatment. Atorvastatin also upregulated Akt/GSK3β phosphorylation in the renal cortex of db/db mice. Our findings suggest that atorvastatin attenuates diabetes-associated renal injury by reducing ROS generation, RhoA activity and normalizing Akt/GSK3β signaling pathways. The present study provides some new insights into molecular mechanisms whereby statins may protect against renal injury in diabetes.

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Targeting of Rho Kinase Ameliorates Impairment of Diabetic Endothelial Function in Intrarenal Artery

Cited by 8 publications

References 39 publications

Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1

Augmented contractility of murine femoral arteries in a streptozotocin diabetes model is related to increased phosphorylation of MYPT1

Targeting endothelial metaflammation to counteract diabesity cardiovascular risk: Current and perspective therapeutic options

Renoprotective Effects of Atorvastatin in Diabetic Mice: Downregulation of RhoA and Upregulation of Akt/GSK3

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