The axis of local cardiac endogenous Klotho-TGF-β1-Wnt signaling mediates cardiac fibrosis in human

Liu, Qinghua; Zhu, Lang-Jing; Waaga-Gasser, Ana Maria; Ding, Yan; Cao, Minghua; Jadhav, Shreyas; Kirollos, Sandra; Shekar, Prem; Padera, Robert F.; Chang, Yu-Chun; Xu, Xingbo; Zeisberg, Elisabeth M.; Charytan, David M.; Hsiao, Li‐Li

doi:10.1016/j.yjmcc.2019.09.004

Cited by 37 publications

(20 citation statements)

References 46 publications

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“…This in turn upregulated Wnt signaling, a major pathway in fibrosis. This was confirmed by in vitro studies with cardiomyocytes, where upregulation of endogenous Klotho inhibited Wnt/β-catenin signaling [50].…”

Section: Growth Factorsmentioning

confidence: 72%

Cardiac Remodeling in Chronic Kidney Disease

Kaesler

Babler

Floege

et al. 2020

Toxins

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Cardiac remodeling occurs frequently in chronic kidney disease patients and affects quality of life and survival. Current treatment options are highly inadequate. As kidney function declines, numerous metabolic pathways are disturbed. Kidney and heart functions are highly connected by organ crosstalk. Among others, altered volume and pressure status, ischemia, accelerated atherosclerosis and arteriosclerosis, disturbed mineral metabolism, renal anemia, activation of the renin-angiotensin system, uremic toxins, oxidative stress and upregulation of cytokines stress the sensitive interplay between different cardiac cell types. The fatal consequences are left-ventricular hypertrophy, fibrosis and capillary rarefaction, which lead to systolic and/or diastolic left-ventricular failure. Furthermore, fibrosis triggers electric instability and sudden cardiac death. This review focuses on established and potential pathophysiological cardiorenal crosstalk mechanisms that drive uremia-induced senescence and disease progression, including potential known targets and animal models that might help us to better understand the disease and to identify novel therapeutics.

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Section: Growth Factorsmentioning

confidence: 72%

Cardiac Remodeling in Chronic Kidney Disease

Kaesler

Babler

Floege

et al. 2020

Toxins

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“…So, revealing interaction between TGF-β and autophagy can be of importance for developing therapeutics. The interesting point is that TGF-β can affect various molecular pathways in disease development including mTOR (Chen et al, 2020c), PI3K/Akt (Wang et al, 2020a), Wnt (Liu et al, 2019), and STAT3 (Dees et al, 2020). There are also molecular pathways that can function as upstream mediators of TGF-β in pathological events.…”

Section: The Role Of Transforming Growth Factor-beta In Pathologicalmentioning

confidence: 99%

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

et al. 2020

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Immune response, proliferation, migration and angiogenesis are juts a few of cellular events that are regulated by transforming growth factor-β (TGF-β) in cells. A number of studies have documented that TGF-β undergoes abnormal expression in different diseases, e.g., diabetes, cancer, fibrosis, asthma, arthritis, among others. This has led to great fascination into this signaling pathway and developing agents with modulatory impact on TGF-β. Curcumin, a natural-based compound, is obtained from rhizome and roots of turmeric plant. It has a number of pharmacological activities including antioxidant, anti-inflammatory, anti-tumor, anti-diabetes and so on. Noteworthy, it has been demonstrated that curcumin affects different molecular signaling pathways such as Wnt/β-catenin, Nrf2, AMPK, mitogen-activated protein kinase and so on. In the present review, we evaluate the potential of curcumin in regulation of TGF-β signaling pathway to corelate it with therapeutic impacts of curcumin. By modulation of TGF-β (both upregulation and down-regulation), curcumin ameliorates fibrosis, neurological disorders, liver disease, diabetes and asthma. Besides, curcumin targets TGF-β signaling pathway which is capable of suppressing proliferation of tumor cells and invading cancer cells.

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“…Recent study showed that Klotho protein can protect Ang II-induced cardiac remodeling through regulating TGF-β-miR-132 axis. Liu et al [78] reported that Klotho is expressed in human atrial appendage tissues. Further, Klotho knockdown or overexpression in primary human cardiomyocytes aggravates or mitigates TGF-β1-induced cardiac fibrosis and activation of the Wnt signaling.…”

Section: The Role Of Klotho In Ckd-induced Cvdmentioning

confidence: 99%

The Protective Role of Klotho in CKD-Associated Cardiovascular Disease

Yang

Zhang

et al. 2020

Kidney Dis

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Background: Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in advanced CKD. The major pathological changes of CKD-associated CVD are severe vascular media calcification, aberrant cardiac remodeling such as hypertrophy and fibrosis, as well as accelerated atherosclerosis. α-Klotho is proposed as an anti-aging gene, which is primarily expressed in the kidney. Recent studies reveal that α-Klotho deficiency is associated with profound cardiovascular dysfunction. Of note, CKD represents extremely declined α-Klotho levels, hinting that α-Klotho deficiency may be implicated in the pathogenesis of CKD-associated CVD. Summary: Based on the pathogenic mechanism of α-Klotho deficiency and decreased Klotho levels in the circulation even early in stage 1 of CKD, α-Klotho serves as a sensitive biomarker for renal insufficiency and also a novel predictor of risk of overall mortality of CVD events in CKD. Meanwhile, loss of Klotho resulted from kidney dysfunction markedly contributes to the progressive development of CKD and CVD. By contrast, prevention of Klotho decline using exogenous supplementation or genetically activated ways by several mechanisms can dramatically mitigate cardiac dysfunction, prevent vascular calcification, and retard the progression of CKD-accelerated atherosclerosis. Key Messages: Klotho deficiency is proposed as a novel predictive biomarker as well as a pathogenic contributor to CVD events in CKD. In the future, Klotho may be a crucial potential therapeutic strategy to decrease the burden of CVD comorbidity with CKD in clinics.

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The axis of local cardiac endogenous Klotho-TGF-β1-Wnt signaling mediates cardiac fibrosis in human

Cited by 37 publications

References 46 publications

Cardiac Remodeling in Chronic Kidney Disease

Cardiac Remodeling in Chronic Kidney Disease

Toward Regulatory Effects of Curcumin on Transforming Growth Factor-Beta Across Different Diseases: A Review

The Protective Role of Klotho in CKD-Associated Cardiovascular Disease

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