Early inflammatory changes and CC chemokine ligand‐8 upregulation in the heart contribute to uremic cardiomyopathy

Amador-Martínez, Isabel; García-Ballhaus, Johannes; Buelna‐Chontal, Mabel; Cortés‐González, Cesar; Massó, Felipe; Jaisser, Frédéric; Barrera‐Chimal, Jonatan

doi:10.1096/fj.202100746r

Cited by 7 publications

(3 citation statements)

References 44 publications

(87 reference statements)

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“…Other upregulated chemokines in Ercc1 Δ/− hearts such as Ccl8 , Ccl11 and Ccl12 and secreted factors such as Retnla have been shown to be involved in the late phase of inflammation ( Yu et al, 2015 ). Ccl8 gene expression under the regulation of NF-κB ( Halle et al, 2010 ) was associated with uremic cardiomyopathy ( Amador-Martínez et al, 2021 ). Ccl11 , or eotaxin, is also known as the protein of senility ( Khavinson et al, 2016 ) and is mainly produced in the heart by the resident fibroblast and the macrophages.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Clavere

Alqallaf

Rostron

et al. 2022

Disease Models &Amp; Mechanisms

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In the heart, ageing is associated with DNA damage, oxidative stress, fibrosis and activation of the activin signalling pathway, leading to cardiac dysfunction. The cardiac effects of activin signalling blockade in progeria are unknown. This study investigated the cardiac effects of progeria induced by attenuated levels of Ercc1 required for DNA excision/repair and the impact of activin signalling blockade using a soluble activin receptor type IIB (sActRIIB). DNA damage and oxidative stress were significantly increased in Ercc1Δ/- hearts but were reduced by sActRIIB treatment. sActRIIB treatment improved cardiac systolic function and induced cardiomyocyte hypertrophy in Ercc1Δ/- hearts. RNA-seq analysis showed that in Ercc1Δ/- hearts there was an increase in pro-oxidant and a decrease in antioxidant gene expression, whilst sActRIIB treatment reversed this. Ercc1Δ/- hearts also expressed higher levels of anti-hypertrophic genes and a decrease in pro-hypertrophic ones which were also reversed by sActRIIB treatment. These results show for the first time that inhibition of activin A receptor signalling attenuates cardiac dysfunction, pathological tissue remodelling and gene expression in Ercc1 deficient mice and presents a potentially novel therapeutic target for heart diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Clavere

Alqallaf

Rostron

et al. 2022

Disease Models &Amp; Mechanisms

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“…Here, we found that daily administration of 10 mg/Kg/day Tac (Tac-10) for 10 days was associated with high blood pressure, an increase in plasma creatinine, and renal damage, represented by the induction in IL-6 and NGAL, two mediators linked to the proinflammatory status [ 45 , 46 , 47 , 48 ]. The dose of Tac used was several times higher than the dose administered to transplant patients [ 49 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

et al. 2023

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Tacrolimus (Tac) is a calcineurin inhibitor commonly used as an immunosuppressor after solid organ transplantation. However, Tac may induce hypertension, nephrotoxicity, and an increase in aldosterone levels. The activation of the mineralocorticoid receptor (MR) is related to the proinflammatory status at the renal level. It modulates the vasoactive response as they are expressed on vascular smooth muscle cells (SMC). In this study, we investigated whether MR is involved in the renal damage generated by Tac and if the MR expressed in SMC is involved. Littermate control mice and mice with targeted deletion of the MR in SMC (SMC-MR-KO) were administered Tac (10 mg/Kg/d) for 10 days. Tac increased the blood pressure, plasma creatinine, expression of the renal induction of the interleukin (IL)-6 mRNA, and expression of neutrophil gelatinase-associated lipocalin (NGAL) protein, a marker of tubular damage (p < 0.05). Our study revealed that co-administration of spironolactone, an MR antagonist, or the absence of MR in SMC-MR-KO mice mitigated most of the unwanted effects of Tac. These results enhance our understanding of the involvement of MR in SMC during the adverse reactions of Tac treatment. Our findings provided an opportunity to design future studies considering the MR antagonism in transplanted subjects.

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“…Uremic cardiomyopathy (UCM) is a common complication in patients with chronic kidney disease (CKD), especially dialysis patients, which is associated with high mortality ( Amador-Martínez et al, 2021 ). The characteristic pathological changes of UCM are left ventricular hypertrophy (LVH) and diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) phase.…”

Section: Introductionmentioning

confidence: 99%

Hydrogen sulfide alleviates uremic cardiomyopathy by regulating PI3K/PKB/mTOR-mediated overactive autophagy in 5/6 nephrectomy mice

Feng

Wang

2022

Front. Pharmacol.

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The gasotransmitter hydrogen sulfide (H2S) plays important physiological and pathological roles in the cardiovascular system. However, the involvement of H2S in recovery from uremic cardiomyopathy (UCM) remains unclear. This study aimed to determine the therapeutic efficacy and elucidate the underlying mechanisms of H2S in UCM. A UCM model was established by 5/6 nephrectomy in 10-week-old C57BL/6 mice. Mice were treated with sodium hydrosulfide (NaHS, H2S donor), L-cysteine [L-Cys, cystathionine gamma-lyase (CSE) substrate], and propargylglycine (PPG, CSE inhibitor). Treatment of H9C2 cardiomyocytes utilized different concentrations of uremic serum, NaHS, PPG, and PI3K inhibitors (LY294002). Mouse heart function was assessed by echocardiography. Pathological changes in mouse myocardial tissue were identified using hematoxylin and eosin and Masson’s trichrome staining. Cell viability was assessed using the Cell Counting Kit-8. The protein expressions of CSE, p-PI3K, PI3K, p-PKB, PKB, p-mTOR, mTOR, and autophagy-related markers (Beclin-1, P62, and LC3) were detected using Western blotting. We found that NaHS and L-Cys treatment attenuated myocardial disarray, fibrosis, and left ventricular dysfunction in UCM mice. These abnormalities were further aggravated by PPG supplementation. Enhanced autophagy and decreased phosphorylation of PI3K, PKB, and mTOR protein expression by UCM were altered by NaHS and L-Cys treatment. In vitro, uremic serum increased overactive autophagy and decreased the phosphorylation levels of PI3K, PKB, and mTOR in cardiomyocytes, which was substantially exacerbated by endogenous H2S deficiency and attenuated by pre-treatment with 100 µm NaHS. However, the protective effects of NaHS were completely inhibited by LY294002. These findings support a protective effect of H2S exerted against UCM by reducing overactive autophagy through activation of the PI3K/PKB/mTOR pathway.

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Early inflammatory changes and CC chemokine ligand‐8 upregulation in the heart contribute to uremic cardiomyopathy

Cited by 7 publications

References 44 publications

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

The Mineralocorticoid Receptor on Smooth Muscle Cells Promotes Tacrolimus-Induced Renal Injury in Mice

Hydrogen sulfide alleviates uremic cardiomyopathy by regulating PI3K/PKB/mTOR-mediated overactive autophagy in 5/6 nephrectomy mice

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