Sphingosine kinase 1 mediates diabetic renal fibrosis via NF-κB signaling pathway: involvement of CK2α

Huang, Junying; Li, Jingyan; Chen, Zhiquan; Li, Jie; Chen, Qiuhong; Gong, Wenyan; Liu, Peiqing; Huang, Heqing

doi:10.18632/oncotarget.21640

Cited by 12 publications

(11 citation statements)

References 53 publications

(48 reference statements)

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“…Previous studies reported that NF-κB signaling pathway is involved in chronic kidney disease, which mediated inflammation and renal fibrosis 41. Such as protein kinase CK2α and sphingosine kinase 1 ameliorate diabetic renal inflammatory fibrosis through the NF-κB pathway 42,43. In the present study, silibinin decreased the upregulation of phosphorylation of IκB and P65 induced by TGF-β1.…”

Section: Discussionsupporting

confidence: 60%

<p>Silibinin attenuates high-fat diet-induced renal fibrosis of diabetic nephropathy</p>

K¹,

Zhou²,

Liu³

et al. 2019

DDDT

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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Silibinin is a flavonoid compound which has medicinal value. Previous studies revealed that silibinin exhibited an anti-fibrotic effect. However, whether silibinin could attenuate high-fat diet (HFD)-induced renal fibrosis remains unclear. Therefore, this study aimed to explore the molecular mechanism by which silibinin regulated renal fibrosis induced by HFD. Methods: In the present study, human renal glomerular endothelial cells (HRGECs) were treated with various concentrations of silibinin. Then, cell viability and apoptosis were measured by MTT assay and flow cytometry, respectively. In addition, HRGECs were exposed to 100 nM TGF-β1 for mimicking in vitro renal fibrosis. The expressions of collagen I, fibronectin, and α-SMA were detected by reverse transcription-quantitative polymerasechain reaction and Western blot. Protein levels of p-IκB and p-p65 were examined by Western blot; meanwhile, level of NF-κB was measured by immunofluorescence staining. Furthermore, HFD-induced mouse model of renal fibrosis was established. The mouse body weight, fasting glucose, kidney weight/body weight, microalbuminuria, kidney histopathology, and fibrotic area were measured to assess the severity of renal fibrosis. Results: Low concentration of silibinin (≤50 μM) had no cytotoxicity, while high concentration of silibinin (≥75 μM) exhibited significant cytotoxicity. Additionally, TGF-β1 increased the expressions of collagen I, fibronectin, α-SMA, p-IκB, and p-p65 and decreased the level NF-κB, while these effects were notably reversed by 50 μM silibinin. Moreover, both 50 and 100 mg/kg silibinin greatly decreased HFD-induced the upregulation of kidney weight/body weight, microalbuminuria, and fibrotic area. 100 mg/kg silibinin markedly reduced collagen I, fibronectin, and p-p65 expressions in mice renal tissues. Conclusion: Silibinin was able to attenuate renal fibrosis in vitro and in vivo via inhibition of NF-κB. These data suggested that silibinin may serve as a potential agent to alleviate the renal fibrosis of DN.

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Section: Discussionsupporting

confidence: 60%

<p>Silibinin attenuates high-fat diet-induced renal fibrosis of diabetic nephropathy</p>

K¹,

Zhou²,

Liu³

et al. 2019

DDDT

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“… 260 Furthermore, the overexpression of sphingosine kinase 1 was suggested as the mediator of the aberrant CK2 action in the diabetic renal inflammatory fibrosis via NFκB pathway. 261 …”

Section: Ck2 In Human Diseasesmentioning

confidence: 99%

Protein kinase CK2: a potential therapeutic target for diverse human diseases

Borgo

D’Amore

Sarno

et al. 2021

Sig Transduct Target Ther

169

177

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CK2 is a constitutively active Ser/Thr protein kinase, which phosphorylates hundreds of substrates, controls several signaling pathways, and is implicated in a plethora of human diseases. Its best documented role is in cancer, where it regulates practically all malignant hallmarks. Other well-known functions of CK2 are in human infections; in particular, several viruses exploit host cell CK2 for their life cycle. Very recently, also SARS-CoV-2, the virus responsible for the COVID-19 pandemic, has been found to enhance CK2 activity and to induce the phosphorylation of several CK2 substrates (either viral and host proteins). CK2 is also considered an emerging target for neurological diseases, inflammation and autoimmune disorders, diverse ophthalmic pathologies, diabetes, and obesity. In addition, CK2 activity has been associated with cardiovascular diseases, as cardiac ischemia–reperfusion injury, atherosclerosis, and cardiac hypertrophy. The hypothesis of considering CK2 inhibition for cystic fibrosis therapies has been also entertained for many years. Moreover, psychiatric disorders and syndromes due to CK2 mutations have been recently identified. On these bases, CK2 is emerging as an increasingly attractive target in various fields of human medicine, with the advantage that several very specific and effective inhibitors are already available. Here, we review the literature on CK2 implication in different human pathologies and evaluate its potential as a pharmacological target in the light of the most recent findings.

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“…In addition, increased expression of S1PR1/2/5 was found in the spleen from mice with anti-GBM Ab GN [ 203 ]. The expression and activity of SphK1 were increased in diabetic kidney [ 198 , 200 , 204 ], MCs [ 198 , 204 ], RTCs [ 94 ] and VSMC [ 205 ], while SphK2 remained unchanged in diabetic kidney, MCs [ 198 ] and VSMC [ 205 ]. SphK1 was overexpressed in podocyte from diabetic patients, while SphK1-deficient mice developed a more severe DN [ 206 ], suggesting a protective role of SphK1 for podocytopathy in DN.…”

Section: Interaction Between Ros and S1p In Oxidant-induced Kidney In...mentioning

confidence: 99%

“…In contrast, deletion of SphK2 decreased neutrophil infiltration in I/R kidney injury [ 259 ], inflammatory macrophage infiltration [ 204 ], TGF-β1 expression, inflammatory cytokines (MCP-1,TNF-α, chemokine ligands-1; CXCL1, and IL-1β) and increased anti-inflammatory (M2) macrophage infiltration in UUO kidney [ 260 ], ameliorating renal inflammation. In addition, SphK2 with Fyn promoted inflammation via STAT3/Akt, while SphK2 knockout reduced it by inhibiting Fyn-STAT3/Akt but not TGF-β1 [ 54 ].…”

Section: Roles Of Mitochondria and Cell Signaling Pathways For S1p-in...mentioning

confidence: 99%

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

Ueda

2022

IJMS

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Reactive oxygen species (ROS) modulate sphingolipid metabolism, including enzymes that generate ceramide and sphingosine-1-phosphate (S1P), and a ROS-antioxidant rheostat determines the metabolism of ceramide-S1P. ROS induce ceramide production by activating ceramide-producing enzymes, leading to apoptosis, while they inhibit S1P production, which promotes survival by suppressing sphingosine kinases (SphKs). A ceramide-S1P rheostat regulates ROS-induced mitochondrial dysfunction, apoptotic/anti-apoptotic Bcl-2 family proteins and signaling pathways, leading to apoptosis, survival, cell proliferation, inflammation and fibrosis in the kidney. Ceramide inhibits the mitochondrial respiration chain and induces ceramide channel formation and the closure of voltage-dependent anion channels, leading to mitochondrial dysfunction, altered Bcl-2 family protein expression, ROS generation and disturbed calcium homeostasis. This activates ceramide-induced signaling pathways, leading to apoptosis. These events are mitigated by S1P/S1P receptors (S1PRs) that restore mitochondrial function and activate signaling pathways. SphK1 promotes survival and cell proliferation and inhibits inflammation, while SphK2 has the opposite effect. However, both SphK1 and SphK2 promote fibrosis. Thus, a ceramide-SphKs/S1P rheostat modulates oxidant-induced kidney injury by affecting mitochondrial function, ROS production, Bcl-2 family proteins, calcium homeostasis and their downstream signaling pathways. This review will summarize the current evidence for a role of interaction between ROS-antioxidants and ceramide-SphKs/S1P and of a ceramide-SphKs/S1P rheostat in the regulation of oxidative stress-mediated kidney diseases.

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Sphingosine kinase 1 mediates diabetic renal fibrosis via NF-κB signaling pathway: involvement of CK2α

Cited by 12 publications

References 53 publications

<p>Silibinin attenuates high-fat diet-induced renal fibrosis of diabetic nephropathy</p>

<p>Silibinin attenuates high-fat diet-induced renal fibrosis of diabetic nephropathy</p>

Protein kinase CK2: a potential therapeutic target for diverse human diseases

A Rheostat of Ceramide and Sphingosine-1-Phosphate as a Determinant of Oxidative Stress-Mediated Kidney Injury

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