Salusin-β Promotes Vascular Calcification <i>via</i> Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation

Sun, Hai-Jian; Zhang, Feng; Xu, Yu; Sun, Shuhong; Wang, Huiping; Du, Qiong; Gu, Chenxin; Black, Stephen M.; Han, Ying; Tang, Haiyang

doi:10.1089/ars.2019.7723

Cited by 28 publications

(25 citation statements)

References 61 publications

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“…The translocation of p47 phox from the cytosol to the membrane is a critical step for excessive ROS production in diabetic kidneys [54]. Very recently, we found that overexpression of salusin-β promoted the translocation of p47 phox to the membrane and subsequent oxidative stress in VSMCs [55]. As a consequence, it is interesting to explore the effects of salusin-β on the membrane translocation of p47 phox in tubular cells.…”

Section: Resultsmentioning

confidence: 99%

“…It is interesting to know whether oxidative stress is involved in AKI-induced salusin-β upregulations. Based on our previous studies, we found that salusin-β expressions were not affected by ROS production as scavenging ROS had no significant effect on the expressions of salusin-β [28,55], suggesting that the expression of salusin-β is not regulated by ROS. As a consequence, the precise mechanisms by which salusin-β is overexpressed in two different AKI models warrant further studies in the future.…”

Section: Discussionmentioning

confidence: 99%

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Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Wang

et al. 2020

Redox Biology

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Salusin-β is abundantly expressed in many organs and tissues including heart, blood vessels, brain and kidneys. Recent studies have identified salusin-β as a bioactive peptide that contributes to various diseases, such as atherosclerosis, hypertension, diabetes and metabolic syndrome. However, the role of salusin-β in the pathogenesis of acute kidney injury (AKI) is largely unclear. In the present study, we investigated the roles of salusin-β in cisplatin or lipopolysaccharide (LPS)-induced renal injury. Herein, we found that salusin-β expression was upregulated in both renal tubular cells and kidney tissues induced by both cisplatin and LPS. In vitro, silencing of salusin-β diminished, whereas overexpression of salusin-β exaggerated the increased PKC phosphorylation, oxidative stress, histone γH2AX expression, p53 activation and apoptosis in either cisplatin or LPS-challenged renal tubular cells. More importantly, salusin-β overexpression-induced tubular cell apoptosis were abolished by using the PKC inhibitor Go 6976, reactive oxygen species (ROS) scavenger NAC, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin (Apo) or p53 inhibitor Pifithrin-α. In animals, blockade of salusin-β alleviated PKC phosphorylation, ROS accumulation, DNA damage, and p53 activation as well as renal dysfunction in mice after administration of cisplatin or LPS. Taken together, these results suggest that overexpressed salusin-β is deleterious in AKI by activation of the PKC/ROS signaling pathway, thereby priming renal tubular cells for apoptosis and death.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Wang

et al. 2020

Redox Biology

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“…The deficiency of the klotho gene has been reported to upregulate the osteogenic transcription factor Runx2 in aortic valves through the adenosine monophosphate kinase-α pathway (36). Oxidative stress, a common risk factor for chronic kidney disease, diabetes mellitus, atherosclerosis and aging, may downregulate the expression of endogenous klotho protein to promote vascular calcification (37). Thus, the above-mentioned results support a possible role of klotho deficiency in regulating vascular calcification.…”

Section: Effects Of Klotho Deficiency On Stem Cells and Vascular Calcmentioning

confidence: 75%

Roles of klotho and stem cells in mediating vascular calcification (Review)

Yu¹,

Li²

2020

Exp Ther Med

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Vascular calcification, characterized by the active deposition of calcium phosphate in the vascular walls, is commonly observed in aging, diabetes mellitus and chronic kidney disease. This process is mediated by different cell types, including vascular stem/progenitor cells. The anti-aging protein klotho may act as an inhibitor of vascular calcification through direct effects on vascular stem/progenitor cells with osteogenic differentiation potential. A better understanding of the possible effects of klotho on vascular stem/progenitor cells may provide novel insight into the cellular and molecular mechanisms of klotho deficiency-related vascular calcification and disease. The klotho protein may be considered as a promising therapeutic agent for treating vascular calcification and disease and calcification-related vascular diseases. Contents

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“…Additionally, in rat aortas, overexpression of salusin-β increased the expression of the NAD(P)H oxidase subunits and NOX2 as well as intensified the production of malondialdehyde and hydrogen peroxide as oxidative stress markers. Combined, the results suggested that the increase in vascular calcification by salusin-β is due to the activation of the NAD(P)H oxidase-ROS pathway [46].…”

Section: Inflammation and Oxidative Stressmentioning

confidence: 88%

“…Overexpression of the peptide salusin-β, shown to be increased in patients undergoing hemodialysis [47], increased calcification of human VSMC and rat aortic rings, not only in calcification media, but also in media without calcification stimulation, as demonstrated by calcium content, alizarin red, or von Kossa staining as well as ALP activity. In parallel, salusin-β increased expression of the osteogenic markers BMP2 and RUNX2, while decreasing expression of contractile SMC markers alpha-smooth muscle actin (α-SMA) and smooth muscle protein 22-alpha (SM22-α) in human VSMC [46]. In contrast, soluble cytokine receptors sTNFR-1 and -2 [48] and sIL-2R [48] did not increase ALP activity nor calcification extent in alizarin red staining when added to human VSMC in pro-calcifying medium.…”

Section: Middle Molecular Weight Substances Increased In Blood In Ckmentioning

confidence: 99%

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

Holmar

Puente-Secades

Floege

et al. 2020

Cells

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Cardiovascular calcification is highly prevalent and associated with increased morbidity in chronic kidney disease (CKD). This review examines the impact of uremic toxins, which accumulate in CKD due to a failing kidney function, on cardiovascular calcification. A systematic literature search identified 41 uremic toxins that have been studied in relation to cardiovascular calcification. For 29 substances, a potentially causal role in cardiovascular calcification was addressed in in vitro or animal studies. A calcification-inducing effect was revealed for 16 substances, whereas for three uremic toxins, namely the guanidino compounds asymmetric and symmetric dimethylarginine, as well as guanidinosuccinic acid, a calcification inhibitory effect was identified in vitro. At a mechanistic level, effects of uremic toxins on calcification could be linked to the induction of inflammation or oxidative stress, smooth muscle cell osteogenic transdifferentiation and/or apoptosis, or alkaline phosphatase activity. For all middle molecular weight and protein-bound uremic toxins that were found to affect cardiovascular calcification, an increasing effect on calcification was revealed, supporting the need to focus on an increased removal efficiency of these uremic toxin classes in dialysis. In conclusion, of all uremic toxins studied with respect to calcification regulatory effects to date, more uremic toxins promote rather than reduce cardiovascular calcification processes. Additionally, it highlights that only a relatively small part of uremic toxins has been screened for effects on calcification, supporting further investigation of uremic toxins, as well as of associated post-translational modifications, on cardiovascular calcification processes.

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Salusin-β Promotes Vascular Calcification via Nicotinamide Adenine Dinucleotide Phosphate/Reactive Oxygen Species-Mediated Klotho Downregulation

Cited by 28 publications

References 61 publications

Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Roles of klotho and stem cells in mediating vascular calcification (Review)

Uremic Toxins Affecting Cardiovascular Calcification: A Systematic Review

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