MicroRNA-92a Mediates Endothelial Dysfunction in CKD

Shang, Fenqing; Wang, Shen-Chih; Hsu, Chien Yi; Miao, Yifei; Martin, Marcy; Yang, Yin; Wu, Chuanchen; Wang, Yun Ting; Wu, Gaihong; Chien, Shu; Huang, Hsien Da; Tarng, Der Cherng; Shiu, Yan Ting; Cheung, Alfred K.; Huang, Po Hsun; Chen, Zhe; Shyy, John Y.‐J.

doi:10.1681/asn.2016111215

Cited by 98 publications

(88 citation statements)

References 35 publications

(50 reference statements)

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“…This later finding is in contrast to our results, since a slight increase in GSH in uremic endothelial cells has been observed, which could be a compensatory response against the prooxidant state present in endothelial cells in response to the uremic milieu. However, and in agreement with the previous and another study, uremic endothelial dysfunction was improved by NAC [28,35], as well as by ebselen. Furthermore, the combined effect of ebselen and NAC on GSH levels were additive in uremic endothelial cells, suggesting a beneficial effect of enhancing the GPx pathway in CKD-induced ED.…”

Section: Discussionsupporting

confidence: 93%

“…A recent systematic review [25] of clinical trials, assessing the effects of antioxidant therapy in CKD patients, indicates that N-acetylcysteine (NAC) has promising effects by decreasing the levels of oxidative stress markers and in a small study it reduced the risk of cardiovascular events in dialysis patients [26]. Furthermore, NAC improves endothelial dysfunction in dialysis patients [27] and in an in vitro model of uremic dysfunction [28].…”

Section: Introductionmentioning

confidence: 99%

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Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

Vera

Torramadé-Moix

Martin-Rodriguez

et al. 2018

Cell Physiol Biochem

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Background/Aims: Accelerated atherosclerosis in chronic kidney disease (CKD) is preceded by endothelial dysfunction (ED), which exhibits a proinflammatory and prothrombotic phenotype and enhanced oxidative stress. In this study, the effect of several compounds with anti-inflammatory and/or antioxidant properties on uremia-induced endothelial dysfunction has been evaluated in an in vitro model. Methods: Endothelial cells (ECs) were exposed to sera from uremic patients in the absence and presence of the flavonoids apigenin, genistein and quercetin, the antioxidant enzyme mimetics (AEM) ebselen (glutathione peroxidase mimetic), EUK-134 and EUK-118 (both superoxide dismutase mimetics), and the pharmacological drug N-acetylcysteine (NAC). We explored changes in the expression of adhesion receptors on the cell surface, by immunofluorescence, the production of radical oxygen species (ROS), by fluorescence detection, and the activation of signaling proteins related to inflammation, by both a phosphospecific antibody cell-based ELISA and immunoblotting techniques. Results: Uremic media induced a significantly increased expression of ICAM-1, overproduction of radical oxygen species (ROS) and activation of p38 mitogen activated protein kinase (p38MAPK) and Nuclear Factor kB (NFkB) in ECs. Quercetin, the AEM and NAC showed a significant inhibitory effect on both ICAM-1 expression and ROS generation (p<0.05). All the compounds reduced p38MAPK activation, but only the AEM, especially ebselen, and NAC, both potentiating the glutathione peroxidase pathway, also inhibited NFkB activation. These two compounds were capable of increasing endothelial glutathione levels, especially in response to uremia. Conclusion: Our results indicate that the potentiation of the antioxidant pathways can be an effective strategy to improve endothelial dysfunction in uremia and a potential target to reduce the cardiovascular risk in this population.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

Vera

Torramadé-Moix

Martin-Rodriguez

et al. 2018

Cell Physiol Biochem

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“…Uremic toxins may induce various pathophysiological effects promoting the release or inhibition of different miRs. Recently, Shang et al [29] demonstrated that increased levels of miR-92a in serum correlated with impaired kidney function. The authors have shown that treatment of endothelial cells (EC) with uremic serum or uremic toxins (such as IS) led to up-regulation of miR-92a with a parallel reduction of miR-92a targets [29].…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Shang et al [29] demonstrated that increased levels of miR-92a in serum correlated with impaired kidney function. The authors have shown that treatment of endothelial cells (EC) with uremic serum or uremic toxins (such as IS) led to up-regulation of miR-92a with a parallel reduction of miR-92a targets [29]. Such a decreased expression of key protective molecules resulting in impaired function of EC may predispose to the development of progressive atherosclerosis and cardiovascular events.…”

Section: Discussionmentioning

confidence: 99%

Circulating miR-421 Targeting Leucocytic Angiotensin Converting Enzyme 2 Is Elevated in Patients with Chronic Kidney Disease

Trojanowicz

Imdahl²,

Ulrich

et al. 2018

Nephron

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Background: Decreased levels of leucocytic angiotensin converting enzyme 2 (ACE2) relate to atherosclerosis in patients with chronic kidney disease (CKD). Recently, micro RNA 421 (miR-421) was found to target and down-regulate ACE2 in human cardiac myofibroblasts. In this study, we investigated the correlation between serum levels of miR-421 and ACE2 transcripts in circulating leukocytes of healthy individuals (NP), CKD (3–5) and haemodialysis (HD) patients. Furthermore, we tested the possible interaction between miR-421 and 3′-UTR of ACE2 under normal and uremic milieu. Methods: The levels of circulating miR-421, serum Ang1–7 and expression of leucocytic ACE2, ACE, MASR, AT1R and AT2R were investigated in 16 CKD3–5 (76 ± 10 years), 32 HD patients (65 ± 13 years) and 23 NP (51 ± 5 years) by employment of specific primers, TaqMan and competitive enzyme-linked immunosorbent assay assays. Interaction between miR-421 and ACE2–3′-UTR was investigated on THP-1 cells by employment of normal and uremic sera, reporter vectors and miR-421 inhibitor. Effects of uremic toxins indoxyl sulphate, p-cresol and p-cresyl sulphate on ACE2 and miR-421 levels were investigated in THP-1 monocytes. Results: The levels of serum miR-421 were significantly elevated, while Ang1–7 was significantly decreased in CKD3–5 and HD patients as compared with NP. Serum Ang1–7 correlated positively with leucocytic ACE2 (r² = 0.213, p < 0.001). We found a significant and inverse correlation between the levels of circulating miR-421 and the expression of leucocytic ACE2 (r² = 0.223, p < 0.0001). Further significant and positive correlations could be demonstrated between miR-421 and the transcripts of leucocytic AT1R (r² = 0.094, p < 0.05) or eGFR (r² = 0.231, p < 0.0001) or CRP (r² = 0.092, p < 0.01). We found no correlations between miR-421 and ACE or AT2R or MASR expression. Treatment with miR-421 or uremic serum led to noticeable decrease of reporter 3′UTR-ACE2. Anti-miR-421 treatment resulted in the up-regulation of ACE2 protein. All uremic toxins tested were able to significantly elevate miR-421 levels and decrease the monocytic ACE2 transcripts. Conclusions: Uremic patients show an enhanced expression of serum miR-421 as compared to healthy individuals. A strong association of circulating miR-421 with decreased transcripts of ACE2 may contribute to the low expression of the enzyme in leukocytes of CKD patients, further supporting the development of atherosclerotic events.

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“…Indole is then absorbed via gut villi and enters the portal system of liver, where it is sulphated and metabolized into IS. Indoxyl sulphate is a protein‐bound small molecule uremic toxin and is harmful for various cells, particularly vascular endothelial cells . In CKD patients, the excretion of IS is impaired, and it is thus accumulated in the body and leads to a vicious cycle .…”

Section: Indoxyl Sulphate a Uremic Toxin Originated From Human Gutmentioning

confidence: 99%

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients

Yang

Tarng

2018

Nephrology

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Emerging evidence suggests that intestinal dysbiosis plays an important role in host inflammation locally and systemically. Such pathological condition is even more prevailing in patients with chronic kidney disease (CKD). Of note, indoxyl sulphate (IS), a gut‐derived uremic toxin, is notorious for its pro‐inflammatory feature in CKD patients. IS accumulates in the body as the urinary excretion of uremic toxins is impaired, and further worsens the kidney function in a vicious cycle to CKD. Dietary restriction in vegetables, fruits and yogurt leads to the predominance of indole‐producing intestinal microbial flora and further exaggerates the accumulation of IS in CKD patients. Recently, interventional studies have shown that circulating IS can be reduced by dietary prebiotic and/or probiotic supplements. However, further randomized controlled trials are warranted to examine whether such beneficial effect of dietary prebiotic/probiotic supplements could be extrapolated to better hard outcomes in CKD population. In this review, we would also like to emphasize the importance of achieving sufficient intake of dietary fibre by proper vegetable pre‐treatment and accurate fruit selection, instead of directly avoiding these potassium‐rich yet fibre‐rich and base‐producing foods.

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MicroRNA-92a Mediates Endothelial Dysfunction in CKD

Cited by 98 publications

References 35 publications

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

Antioxidant and Anti-Inflammatory Strategies Based on the Potentiation of Glutathione Peroxidase Activity Prevent Endothelial Dysfunction in Chronic Kidney Disease

Circulating miR-421 Targeting Leucocytic Angiotensin Converting Enzyme 2 Is Elevated in Patients with Chronic Kidney Disease

Diet, gut microbiome and indoxyl sulphate in chronic kidney disease patients

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