α-Klotho released from HK-2 cells inhibits osteogenic differentiation of renal interstitial fibroblasts by inactivating the Wnt–β-catenin pathway

Zhu, Zewu; Ruan, Shuhao; Jiang, Yingcheng; Huang, Fang; Xia, Weiliang; Chen, Jinbo; He, Cheng; Yang, Li; Chen, Zhiyong; Chen, Hequn

doi:10.1007/s00018-021-03972-x

Cited by 10 publications

(14 citation statements)

References 54 publications

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“…Considering that incipient calcium deposits partially appeared in renal interstitium which was far apart from these cells with a tubular structure (Fig. 1 B); renal interstitial calcium deposits were reported to grow by the addition of crystals on the periphery within a collagen framework (Khan et al 2012 ), and the osteogenic capability of hRIFs was significantly stronger than that of tubular epithelial cells as revealed by our previous study (Zhu et al 2021 ), we wondered whether OCT4 and osteogenic markers were altered in renal interstitial fibroblasts. Intriguingly, immunofluorescence co-staining showed that fibroblast marker Vimentin was partially co-localized with upregulated OCT4 (Fig.…”

Section: Resultsmentioning

confidence: 60%

“…As described by our previous study (Zhu et al 2021 ), semi-quantitative analysis was performed for IHC staining and the co-localization ratio in immunofluorescence. Briefly, IHC staining was analyzed using the “IHC Toolbox” plugin in Image J (Shu et al 2016 ), and the co-localization ratio was calculated by the confocal microscope system (Leica TCS SP8 X, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, the structure of RP presents somewhat similarities to physiological bone formation as well as pathological biominerals driven by osteogenic-like cells (Khan and Gambaro 2007 ; Gay et al 2020 ; Zhu et al 2020a ). Though significant progress has been achieved in the nanoscale analysis of RP over the last decades (Gay et al 2020 ; Verrier et al 2016 ; Evan et al 2003a ), and renal tubular epithelial cells, as well as renal interstitial fibroblasts, were reported to successfully form CaP crystal depositions (Priante et al 2019 ; Zhu et al 2021 ) under osteogenic induction, the mechanism underlying the very first step of CaP formation, one of the speculative ways in which some cells adopted osteogenic-like phenotype, remains poorly understood in RP formation.…”

Section: Introductionmentioning

confidence: 99%

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OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall’s plaque formation

Zhu

Huang

Jiang

et al. 2022

Mol Med

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Background Randall’s plaques (RP) are identified as anchored sites for kidney calcium oxalate stones, but the mechanism remains unclear. Given the importance of osteogenic-like cells in RP formation and OCT4 in reprogramming differentiated cells to osteoblasts, the current study explored the potential role of OCT4 in RP formation. Methods OCT4 and biomineralization were evaluated in RP, and immunofluorescence co-staining was performed to identify these cells with alteration of OCT4 and osteogenic markers. Based on the analysis of tissue, we further investigated the mechanism of OCT4 in regulating osteogenic-like differentiation of primary human renal interstitial fibroblasts (hRIFs) in vitro and vivo. Results We identified the upregulated OCT4 in RP, with a positive correlation to osteogenic markers. Interestingly, fibroblast marker Vimentin was partially co-localized with upregulated OCT4 and osteogenic markers in RP. Further investigations revealed that OCT4 significantly enhanced the osteogenic-like phenotype of hRIFs in vitro and in vivo. Mechanically, OCT4 directly bound to BMP2 promoter and facilitated its CpG island demethylation to transcriptionally promote BMP2 expression. Furthermore, combination of RIP and RNA profiling uncovered that lncRNA OLMALINC physically interacted with OCT4 to promote its stabilization via disrupting the ubiquitination. Additionally, OLMALINC was upregulated in fibroblasts in RP visualized by FISH, and a positive correlation was revealed between OLMALINC and OCT4 in RP. Conclusions The upregulation of OCT4 in hRIFs was a pathological feature of RP formation, and OLMALINC/OCT4/BMP2 axis facilitated hRIFs to acquire osteogenic-like phenotype under osteogenic conditions, through which the pathway might participate in RP formation. Our findings opened up a new avenue to better understand RP formation in which osteogenic-like process was partially triggered by lncRNAs and pluripotency maintenance related genes.

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Section: Resultsmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall’s plaque formation

Zhu

Huang

Jiang

et al. 2022

Mol Med

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“…However, no data to date are available about the mechanism of IKKα on inducing kidney fibrosis. As is known that Wnt/β‐catenin pathway is involved in kidney fibrosis [37–45], our studies found active‐β‐catenin and snail were markedly increased in UIRI and UUO models which were down‐regulated when IKKα was knocked out, indicating that knockout of IKKα gene inhibits activation of wnt/β‐catenin pathway. In addition, the binding of IKKα and β‐catenin was studied in vitro.…”

Section: Discussionmentioning

confidence: 61%

IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β‐catenin pathway

et al. 2022

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AKI (acute kidney injury) with maladaptive repair plays exacerbated role in renal fibrosis characterized by tubulointerstitial fibrosis. Previously, we reported that IKKα contributed to kidney regeneration and inhibited inflammation. Here, we first identified the role and mechanism of IKKα on TGF-β1-induced fibrosis in human tubular epithelial cells and fibrotic kidneys. IKKα was up-regulated in kidney tubular epithelium in unilateral ureteral obstruction (UUO) and unilateral ischemic reperfusion injury (UIRI) mice. Immunohistochemical staining showed that IKKα was positively correlated with the extent of kidney fibrosis in tissue biopsies from chronic kidney disease (CKD) patients. Compared with wild-type controls, Ksp-IKKα À/À mice exhibited inactivated Wnt/β-catenin pathway, decreased serum creatinine and interstitial fibrosis in the kidney after IRI. In TGF-β1-stimulated human tubular epithelial cells, IKKα overexpression enhanced β-catenin nuclear translocation. Blocking IKKα by siRNA specifically suppressed β-catenin activation and downstream profibrotic genes such as fibronectin and α-smooth muscle actin (α-SMA). Taken together, our study demonstrated that IKKα aggravated renal fibrogenesis by activating Wnt/β-catenin signalling pathway, providing a new target for the treatment of kidney fibrosis.

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“…The Wnt/β-catenin pathway is an evolutionarily conserved developmental signalling cascade that plays a pivotal role in regulating organ development and formation, tissue homeostasis and disease progression ( Garg and Maurya, 2019 ; Zhu et al, 2021 ). Wnt/β-catenin signalling is relatively silent in the absence of Wnt ligand, and β-catenin is degraded by ubiquitin proteins after being phosphorylated by protein composites ( Li et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Shenkang injection improves chronic kidney disease by inhibiting multiple renin-angiotensin system genes by blocking the Wnt/β-catenin signalling pathway

et al. 2022

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Chronic kidney disease (CKD) is a major worldwide public health problem. The increase in the number of patients with CKD and end-stage kidney disease requesting renal dialysis or transplantation will progress to epidemic proportions in the next several decades. Although blocking the renin-angiotensin system (RAS) has been used as a first-line standard therapy in patients with hypertension and CKD, patients still progress towards end-stage kidney disease, which might be closely associated with compensatory renin expression subsequent to RAS blockade through a homeostatic mechanism. The Wnt/β-catenin signalling pathway is the master upstream regulator that controls multiple intrarenal RAS genes. As Wnt/β-catenin regulates multiple RAS genes, we inferred that this pathway might also be implicated in blood pressure control. Therefore, discovering new medications to synchronously target multiple RAS genes is necessary and essential for the effective treatment of patients with CKD. We hypothesized that Shenkang injection (SKI), which is widely used to treat CKD patients, might ameliorate CKD by inhibiting the activation of multiple RAS genes via the Wnt/β-catenin signalling pathway. To test this hypothesis, we used adenine-induced CKD rats and angiotensin II (AngII)-induced HK-2 and NRK-49F cells. Treatment with SKI inhibited renal function decline, hypertension and renal fibrosis. Mechanistically, SKI abrogated the increased protein expression of multiple RAS elements, including angiotensin-converting enzyme and angiotensin II type 1 receptor, as well as Wnt1, β-catenin and downstream target genes, including Snail1, Twist, matrix metalloproteinase-7, plasminogen activator inhibitor-1 and fibroblast-specific protein 1, in adenine-induced rats, which was verified in AngII-induced HK-2 and NRK-49F cells. Similarly, our results further indicated that treatment with rhein isolated from SKI attenuated renal function decline and epithelial-to-mesenchymal transition and repressed RAS activation and the hyperactive Wnt/β-catenin signalling pathway in both adenine-induced rats and AngII-induced HK-2 and NRK-49F cells. This study first revealed that SKI repressed epithelial-to-mesenchymal transition by synchronously targeting multiple RAS elements by blocking the hyperactive Wnt/β-catenin signalling pathway.

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α-Klotho released from HK-2 cells inhibits osteogenic differentiation of renal interstitial fibroblasts by inactivating the Wnt–β-catenin pathway

Cited by 10 publications

References 54 publications

OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall’s plaque formation

OLMALINC/OCT4/BMP2 axis enhances osteogenic-like phenotype of renal interstitial fibroblasts to participate in Randall’s plaque formation

IKKα aggravates renal fibrogenesis by positively regulating the Wnt/β‐catenin pathway

Shenkang injection improves chronic kidney disease by inhibiting multiple renin-angiotensin system genes by blocking the Wnt/β-catenin signalling pathway

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