Epigenetic modifications of Klotho expression in kidney diseases

Xia, Jinkun; Cao, Wangsen

doi:10.1007/s00109-021-02044-8

Cited by 21 publications

(17 citation statements)

References 141 publications

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“…In fact, many preclinical studies have elaborated restoration of epigenetic abnormality of Klotho expression provided new therapeutic performance for diverse etiologies of kidney diseases including CKD ( Hu et al, 2016b ; Li et al, 2019b ; Xia and Cao, 2021 ; Kale et al, 2022 ). This indicated that epigenetic regulation of Klotho possibly represents potential directions and contributes to novel therapeutic development for CKD ( Yin et al, 2017 ; Li et al, 2019b ; Kale et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Perhaps STAT3 signaling is not the only way to act in DNMT1-induced Klotho methylation. Because Klotho expression was also controlled by other epigenetic mechanisms, such as histone acetylation (HDAC), transcription factors (TFs), and non-coding RNA ( Kale et al, 2021 ; Xia and Cao, 2021 ). A recent study reported that renal HDAC3 expression was preferentially increased in UUO mice and selective inhibition of HDAC3 derepressed Klotho expression and alleviated RIF ( Chen et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

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CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Liu

et al. 2022

Front. Physiol.

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BackgroundEnhanced inflammation and reduced Klotho are common features in chronic kidney disease (CKD). Inflammation induces DNA hypermethylation. This study assessed the performance of inflammatory marker C-C motif chemokine 5 (CCL5) in epigenetic regulation of Klotho expression.MethodsFifty CKD patients and 25 matched controls were enrolled, and serum CCL5 level, sKlotho level, and DNA methylation were evaluated in these subjects. A renal interstitial fibrosis (RIF) model with CKD was induced in mice via unilateral ureteral obstruction (UUO) in vivo and human proximal tubular epithelial (HK-2) cells treated with CCL5 in vitro. 5-aza-2′-deoxycytidine (5-Aza), a DNA methyltransferase inhibitor was given to UUO mice. Hematoxylin and eosin (HE) and Masson trichrome staining were adopted to evaluate renal pathological changes. Methylation-specific PCR was performed to assess DNA methylation of Klotho promoter in the peripheral blood leucocytes (PBLs) from CKD patients and obstructive kidney from UUO mice. CCL5, Klotho, and DNA methyltransferases (DNMTs) were determined by ELISAs, immunofluorescence, or western blotting. HK-2 cells were exposed to CCL5 with or without 5-Aza and stattic, a p-signal transducer and activator of transcription 3 (STAT3) inhibitor, and expressions of p-STAT3, DNMT1, and Klotho were determined by western blotting.ResultsCCL5 upregulation concomitant with Klotho downregulation in serum and global DNA methylation in PBLs were observed in CKD samples. UUO contributed to severe renal interstitial fibrosis and enhanced expressions of fibrotic markers. Moreover, UUO increased the CCL5 level, induced Klotho promoter methylation, suppressed Klotho level, activated p-STAT3 signaling, and upregulated DNMT1 level. A similar observation was made in HK-2 cells treated with CCL5. More importantly, 5-Aza inhibited UUO-induced Klotho hypermethylation, reversed Klotho, downregulated p-STAT3 expressions, and ameliorated RIF in vivo. The consistent findings in vitro were also obtained in HK-2 cells exposed to 5-Aza and stattic.ConclusionThe CCL5/p-STAT3/DNMT1 axis is implicated in epigenetic regulation of Klotho expression in CKD. This study provides novel therapeutic possibilities for reversal of Klotho suppression by CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Liu

et al. 2022

Front. Physiol.

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“…Klotho deficiency is associated with renal insufficiency ( 19 ). Klotho has been found in various studies to protect kidneys from loss of function ( 18 ). Meanwhile, acute kidney injury (AKI)/CKD are states of systemic Klotho deficiency, making Klotho a sensitive biomarker of impaired renal function ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

“…Klotho is closely associated with the pathogenesis of CKD. Recently, increasing evidence has shown that Klotho levels are lower in patients and animal models with renal insufficiency ( 18 , 19 ), even though glomerular filtration rate (GFR) is only slightly decreased ( 20 ). In individuals with CKD, lower Klotho levels can be caused by a decrease in functional nephrons and inhibition of Klotho expression; however, Wnt/β-catenin activation is also regarded as a crucial component in Klotho reduction ( 21 ).…”

Section: Introductionmentioning

confidence: 99%

Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals

Zhu

Yin

et al. 2022

Front. Cardiovasc. Med.

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ObjectiveUsing a newly released National Health and Nutrition Examination Survey (NHANES) data of serum Klotho, this study aimed to explore the relationship between Klotho and specific cardiovascular diseases (CVD), as well as the mediation effect of renal function, among middle-aged and older individuals within the general population.MethodsThis nationally representative cross-sectional study analyzed data from the 2007–2016 NHANES. A total of 13,765 participants, who aged 40 years or older, from the general population were examined. Klotho were divided into four groups based on median and interquartile range. The associations among Klotho (exposure), congestive heart failure (CHF; outcome), and renal function markers [estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), uric acid (UA), and urine albumin-to-creatinine ratio (UACR); mediators] were investigated using mediation analysis.ResultsIn comparison to the lowest quartile, Klotho in the highest quartile was independently associated with the prevalence of CHF (OR 0.59; 95% CI 0.46–0.77, p for trend = 0.001), but not with other individual CVDs. Klotho had a significant direct effect on the prevalence of CHF (all p < 0.001), while eGFR, BUN, UA, and UACR partly mediated the indirect effect of Klotho on the prevalence of CHF (all p < 0.05), explaining 19.51, 6.98, 13.93, and 0.71% of the association between Klotho and CHF, respectively. Additionally, restricted cubic spline regression demonstrated a linear association and negative correlation between Klotho level and CHF.ConclusionThese findings suggest that Klotho is closely linked to CHF and renal function may be a key mediator of this association.

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“…Klotho serves a key role in regulating various cellular processes by interacting with multiple signaling molecules, including oxidative stress, fibrosis, inflammation, autophagy, and apoptosis (Hu et al, 2013). Therefore, Klotho is a critical gene, controlling aging and kidney homeostasis, and an ideal intervention target for various kidney diseases and even extrarenal complications (Xia and Cao, 2021). Furthermore, Klotho plays an important role in antifibrotic activities by inhibiting oxidative stress and excessive inflammation.…”

Section: Klothomentioning

confidence: 99%

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

Sun

Hua

et al. 2021

Front. Pharmacol.

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The Wnt/β-catenin signaling pathway plays important roles in embryonic development and tissue homeostasis. Wnt signaling is induced, and β-catenin is activated, associated with the development and progression of renal fibrosis. Wnt/β-catenin controls the expression of various downstream mediators such as snail1, twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1, transient receptor potential canonical 6, and renin-angiotensin system components in epithelial cells, fibroblast, and macrophages. In addition, Wnt/β-catenin is usually intertwined with other signaling pathways to promote renal interstitial fibrosis. Actually, given the crucial of Wnt/β-catenin signaling in renal fibrogenesis, blocking this signaling may benefit renal interstitial fibrosis. There are several antagonists of Wnt signaling that negatively control Wnt activation, and these include soluble Fzd-related proteins, the family of Dickkopf 1 proteins, Klotho and Wnt inhibitory factor-1. Furthermore, numerous emerging small-molecule β-catenin inhibitors cannot be ignored to prevent and treat renal fibrosis. Moreover, we reviewed the knowledge focusing on anti-fibrotic effects of natural products commonly used in kidney disease by inhibiting the Wnt/β-catenin signaling pathway. Therefore, in this review, we summarize recent advances in the regulation, downstream targets, role, and mechanisms of Wnt/β-catenin signaling in renal fibrosis pathogenesis. We also discuss the therapeutic potential of targeting this pathway to treat renal fibrosis; this may shed new insights into effective treatment strategies to prevent and treat renal fibrosis.

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Epigenetic modifications of Klotho expression in kidney diseases

Cited by 21 publications

References 141 publications

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

CCL5 Suppresses Klotho Expression via p-STAT3/DNA Methyltransferase1-Mediated Promoter Hypermethylation

Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals

Targeting the Wnt/β-Catenin Signaling Pathway as a Potential Therapeutic Strategy in Renal Tubulointerstitial Fibrosis

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