Klotho inhibits angiotensin II-induced cardiac hypertrophy, fibrosis, and dysfunction in mice through suppression of transforming growth factor-β1 signaling pathway

Ding, Jieqiong; Tang, Qiong; Luo, Bin; Zhang, Lijun; Lin, Liang‐Chuan; Han, Lu; Hao, Miaomiao; Li, Mingyue; Yu, Liangzhu; Li, Mincai

doi:10.1016/j.ejphar.2019.172549

Cited by 55 publications

(40 citation statements)

References 33 publications

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“…FGF23 excess can induce LVH through direct activation of FGFR4 in the heart and indirect effects on the kidney to increase sodium reabsorption, leading to hypertension (46,47,57). In contrast, sKL can prevent LVH caused by angiotensin II-induced cardiac hypertrophy (58,59). Therefore, we investigated whether Kl Tg mice exhibited cardiovascular abnormalities.…”

Section: Resultsmentioning

confidence: 99%

“…Nevertheless, our findings provide additional insights into the pathophysiology of FGF23 and α-Klotho by suggesting that the levels of sKL as well as the tissue expression of mKL 135 , along with levels of circulating FGF23, may determine whether physiological or adverse effects are observed. For example, other studies show that angiotensin II can both enhance cardiac fibrosis (76) and attenuate cardiac hypertrophy in Kl Tg mice (59), possibly due to different roles of membrane and soluble α-Klotho isoforms. Typically, models of FGF23-induced LVH have suppression of α-Klotho (77), suggesting that cardiotoxicity requires elevated FGF23 and reduced sKL.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Xiao¹,

King²,

Mancarella³

et al. 2019

JCI Insight

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Xiao¹,

King²,

Mancarella³

et al. 2019

JCI Insight

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“…It has been largely demonstrated that TGF-beta serves as a key downstream mediator in Ang II-induced chronic renal fibrosis (Iekushi et al, 2011). Fibrosis resulting in the excessive synthesis and accumulation of interstitial matrix proteins could be induced by Ang II via the upregulation of TGF-beta (Ehanire et al, 2015a;Ding et al, 2019). Consistent with these findings, our data showed that following Ang II infusion, the expression of fibrotic markers alpha-SMA, MMP-2, and MMP-9 were all significantly increased (Figures 1A-F).…”

Section: Discussionmentioning

confidence: 99%

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

Zhang

Fan

Cai

et al. 2020

Front. Cell Dev. Biol.

168

130

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Fibrosis is a common phenotype that often leads to the progression of blood pressure-induced chronic kidney disease (CKD). TGF-beta plays an important role in promoting pathogenesis, and NLRP3 is a critical mediator in the progression of blood pressure-induced CKD. However, the pathophysiological roles of the TGF-betamediated NLRP3 pathway in modulating fibrosis in blood pressure-induced CKD have not been elucidated. The present study aims to investigate the contribution of TGFbeta-mediated NLRP3 inflammasome to renal fibrosis in rats with high blood pressure. By treating rats with angiotensin II (Ang II) for 14 days, we observed the development of fibrosis, characterized by epithelial-mesenchymal transition (EMT) markers [alphasmooth muscle actin (alpha-SMA), MMP-2, and MMP-9]. Immunohistochemical analysis further revealed that TGF-beta and NLRP3 inflammasome activation [high-mobility group box 1 (HMGB1), IL-1beta, and NLRP3] were significantly upregulated in the kidney of rats with Ang II-induced hypertension. Interestingly, we observed that Ang II could not increase the production of NLRP3 proteins, but TGF-beta could induce NLRP3 protein expression in cultured NRK-52E cells. Furthermore, we speculated that TGF-beta played a pathogenic role in Ang II-induced CKD because TGF-beta induced the activation of NLRP3 inflammasomes and Gasdermin D cleavage expression. We also proved that the pharmacological inhibition of NLRP3 by ISO caused a decrease in TGF-beta-induced NLRP3 inflammasome activation and the expression of EMT markers (alpha-SMA and CollagenI) and Gasdermin D cleavage. Collectively, these results suggest that TGF-beta-mediated NLRP3 inflammasome activation may cause the release of HMGB1 and an increase in Gasdermin D cleavage in NRK-52E, thereby contributing to renal fibrosis in Ang II-induced CKD. These findings provide novel insights into the pathogenic role of NLRP3 in CKD associated with high blood pressure.

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“…13,14 Ang II-induced cardiac fibrosis is partially attributed to the TGF-β/Smad2/3 pathway. 13,[15][16][17] In contrast, other studies have reported that TGF-β can induce the upregulation of phosphorylated ERK1/2 (p-ERK1/2) in patients with fibrotic disorders. 18,19 These findings suggest that a feedback mechanism may exist between ERK and TGF-β signaling.…”

Section: Introductionmentioning

confidence: 93%

<p>MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation</p>

Li¹,

Mao²,

Zhou³

et al. 2020

JIR

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Post myocardial infarction (MI) fibrosis has been identified as an important factor in the progression of heart failure. Previous studies have revealed that microRNA-21 (miR-21) plays an important role in the pathogenesis of fibrosis. The purpose of this study was to explore the role of miR-21 in post-MI cardiac fibrosis. Material and Methods: MI was established in wild-type (WT) and miR-21 knockout (KO) mice. Primary mice cardiac fibroblasts (CFs) were isolated from WT and miR-21 KO mice and were treated with angiotensin II (Ang II) or Sprouty1 (Spry1) siRNA. Histological analysis and echocardiography were used to determine the extent of fibrosis and cardiac function. Results: Compared with WT mice, miR-21 KO mice displayed smaller fibrotic areas and decreased expression of fibrotic markers and inflammatory cytokines. In parallel, Ang IIinduced myofibroblasts transformation was partially inhibited upon miR-21 KO in primary CFs. Mechanistically, we found that the expression of Spry1, a previously reported target of miR-21, was markedly increased in miR-21 KO mice post MI, further inhibiting ERK1/2 activation. In vitro studies showed that Ang II activated ERK1/2/TGF-β/Smad2/3 pathway. Phosphorylated Smad2/3 further enhanced the expression of α-SMA and FAP and may promote the maturation of miR-21, thereby downregulating Spry1. Additionally, these effects of miR-21 KO on fibrosis were reversed by siRNA-mediated knockdown of Spry1. Conclusion: Our findings suggest that miR-21 promotes post-MI fibrosis by targeting Spry1. Furthermore, it mediates a positive feedback on Ang II, thereby inducing the ERK/ TGF-β/Smad pathway. Therefore, targeting the miR-21-Spry1 axis may be a promising therapeutic option for ameliorating post-MI cardiac fibrosis.

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Klotho inhibits angiotensin II-induced cardiac hypertrophy, fibrosis, and dysfunction in mice through suppression of transforming growth factor-β1 signaling pathway

Cited by 55 publications

References 33 publications

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

FGF23 expression is stimulated in transgenic α-Klotho longevity mouse model

Contribution of TGF-Beta-Mediated NLRP3-HMGB1 Activation to Tubulointerstitial Fibrosis in Rat With Angiotensin II-Induced Chronic Kidney Disease

<p>MicroRNA-21 Mediates a Positive Feedback on Angiotensin II-Induced Myofibroblast Transformation</p>

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