Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Lu, Qing-Bo; Du, Qiong; Wang, Huiping; Tang, Zihan; Wang, Yuan-Ben; Sun, Hai-Jian

doi:10.1016/j.redox.2019.101411

Cited by 44 publications

(37 citation statements)

References 90 publications

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“…Moreover, the therapeutic effects of polysulfide and H 2 S on cisplatin-induced inflammation response were also assessed in mice as inflammation is critically involved in the pathologies of cisplatin nephrotoxicity [ 27 ]. As previously described [ 28 , 29 ], the levels of TNF-α and IL-1β in both serum and renal tissues were significantly enhanced in cisplatin-induced mice, and these upregulated pro-inflammatory cytokines were diminished by Na 2 S 4 , NaHS, and GYY4137 ( Figure 5 A–B). Then, we conducted RT-PCR and immunoblot to testify the expressions of pro-inflammatory cytokines in renal tissues, including TNF-α, IL-1β, IL-6, and COX-2.…”

Section: Resultssupporting

confidence: 78%

“…At the end of animal experiments, the serum samples were collected and the serum BUN and creatinine levels were measured to evaluate kidney function by using commercially available kits (Nanjing Jiancheng Bioengineering Institute, Nanjing, China) in accordance with the manufacturer’s protocols [ 29 , 75 ]. The absorbance for serum BUN was analyzed at 640 nm by a microplate reader.…”

Section: Methodsmentioning

confidence: 99%

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Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

Sun

Leng

et al. 2020

IJMS

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Cisplatin, a widely used chemotherapy for the treatment of various tumors, is clinically limited due to its extensive nephrotoxicity. Inflammatory response in tubular cells is a driving force for cisplatin-induced nephrotoxicity. The plant-derived agents are widely used to relieve cisplatin-induced renal dysfunction in preclinical studies. Polysulfide and hydrogen sulfide (H2S) are ubiquitously expressed in garlic, and both of them are documented as potential agents for preventing and treating inflammatory disorders. This study was designed to determine whether polysulfide and H2S could attenuate cisplatin nephrotoxicity through suppression of inflammatory factors. In renal proximal tubular cells, we found that sodium tetrasulfide (Na2S4), a polysulfide donor, and sodium hydrosulfide (NaHS) and GYY4137, two H2S donors, ameliorated cisplatin-caused renal toxicity through suppression of the massive production of inflammatory cytokines, including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2). Mechanistically, the anti-inflammatory actions of Na2S4 and H2S may be mediated by persulfidation of signal transducer and activator of transcription 3 (STAT3) and inhibitor kappa B kinase β (IKKβ), followed by decreased phosphorylation of STAT3 and IKKβ. Moreover, the nuclear translocation of nuclear transcription factor kappa B (NF-κB), and phosphorylation and degradation of nuclear factor kappa B inhibitor protein alpha (IκBα) induced by cisplatin, were also mitigated by both polysulfide and H2S. In mice, after treatment with polysulfide and H2S donors, cisplatin-associated renal dysfunction was strikingly ameliorated, as evidenced by measurement of serum blood urea nitrogen (BUN) and creatinine levels, renal morphology, and the expression of renal inflammatory factors. Our present work suggests that polysulfide and H2S could afford protection against cisplatin nephrotoxicity, possibly via persulfidating STAT3 and IKKβ and inhibiting NF-κB-mediated inflammatory cascade. Our results might shed light on the potential benefits of garlic-derived polysulfide and H2S in chemotherapy-induced renal damage.

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Section: Resultssupporting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

Sun

Leng

et al. 2020

IJMS

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“…Importantly, the enhanced oxidative stress is predominantly regulated by various NADPH oxidases (NOX) isoforms, including p22 phox , p47 phox and NOX2 in diabetic nephropathy [ 57 ]. The membrane translocation of p47 phox is a fundamental event for the formation of reactive oxygen species (ROS) in both diabetic kidney disease and acute kidney injury [ 58 , 59 ]. In comparison with NG-treated cells, the protein expression levels of p22 phox , p47 phox and NOX2 were augmented in HK-2 cells upon exposure to HG, and this effect was counteracted by preconditioning with Na 2 S 4 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3

et al. 2021

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Diabetic kidney disease is known as a major cause of chronic kidney disease and end stage renal disease. Polysulfides, a class of chemical agents with a chain of sulfur atoms, are found to confer renal protective effects in acute kidney injury. However, whether a polysulfide donor, sodium tetrasulfide (Na 2 S 4 ), confers protective effects against diabetic nephropathy remains unclear. Our results showed that Na 2 S 4 treatment ameliorated renal dysfunctional and histological damage in diabetic kidneys through inhibiting the overproduction of inflammation cytokine and reactive oxygen species (ROS), as well as attenuating renal fibrosis and renal cell apoptosis. Additionally, the upregulated phosphorylation and acetylation levels of p65 nuclear factor κB (p65 NF-κB) and signal transducer and activator of transcription 3 (STAT3) in diabetic nephropathy were abrogated by Na 2 S 4 in a sirtuin-1 (SIRT1)-dependent manner. In renal tubular epithelial cells, Na 2 S 4 directly sulfhydrated SIRT1 at two conserved CXXC domains (Cys371/374; Cys395/398), then induced dephosphorylation and deacetylation of its targeted proteins including p65 NF-κB and STAT3, thereby reducing high glucose (HG)-caused oxidative stress, cell apoptosis, inflammation response and epithelial-to-mesenchymal transition (EMT) progression. Most importantly, inactivation of SIRT1 by a specific inhibitor EX-527, small interfering RNA (siRNA), a de-sulfhydration reagent dithiothreitol (DTT), or mutation of Cys371/374 and Cys395/398 sites at SIRT1 abolished the protective effects of Na 2 S 4 on diabetic kidney insulting. These results reveal that polysulfides may attenuate diabetic renal lesions via inactivation of p65 NF-κB and STAT3 phosphorylation/acetylation through sulfhydrating SIRT1.

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“… 16 , 17 Indeed, salusin-β knockdown reduced cell proliferation, apoptosis, oxidative stress, and inflammation in cisplatin- or LPS-induced renal tubular cells and mice with acute kidney injury; however, salusin-β overexpression reversed these effects. 18 Additionally, another study indicated that salusin-β silencing reduced high glucose (HG)-induced apoptosis by upregulating Bcl-2 expression and downregulating Bax and caspase-3 expression in human umbilical vein endothelial cells. 17 Moreover, other studies revealed that salusin-β blockade alleviated oxidative stress, inflammation, and cardiac dysfunction in diabetic rats.…”

Section: Introductionmentioning

confidence: 99%

Salusin-β Mediates High Glucose-Induced Inflammation and Apoptosis in Retinal Capillary Endothelial Cells via a ROS-Dependent Pathway in Diabetic Retinopathy

Wang¹,

Zhang²,

Zhou³

et al. 2021

DMSO

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Background: Diabetic retinopathy (DR) is characterized by retinal vascular endothelial cell death and vascular inflammation, which are microvascular complications of diabetes mellitus (DM). Salusin-β, a newly identified peptide, is closely associated with hypertension, atherosclerosis and diabetic cardiomyopathy. However, the exact role of salusin-β in high glucose (HG)-induced retinal capillary endothelial cell (REC) inflammation and apoptosis remains unclear.Patients and Methods: A total of 60 patients with type 2 diabetes and 20 healthy controls were included in this study. Based on fundus fluorescein angiography findings, the diabetic patients were divided into three subgroups: diabetes without retinopathy (DWR), nonproliferative DR (NPDR) and proliferative DR (PDR). Serum salusin-β levels were measured by enzyme-linked immunosorbent assay. Human RECs (HRECs) were cultured in normal glucose (NG) and HG medium with or without salusin-β. Salusin-β expression was analysed by Western blotting and immunofluorescence staining. Expression of the pro-inflammatory cytokines MCP-1, IL-1β, TNF-α, and VCAM-1 was analysed by Western blotting. Reactive oxygen species (ROS) production was measured with 2′,7′-dichlorofluorescein diacetate (DCFH-DA). Cell apoptosis rates were determined by flow cytometry. The levels of p38, JNK, p-p38, and p-JNK and the apoptosis-related proteins cleaved caspase-3, Bax, and cl2 were analysed by Western blotting. Results: Serum salusin-β levels were higher in diabetic patients than in healthy controls (p = 0.0027), especially in patients with NPDR and PDR (both p<0.01). HG upregulated salusin-β expression in HRECs in a time-dependent manner. Salusin-β exacerbated inflammation and apoptosis, upregulated intracellular ROS production in HG-induced HRECs, and activated ROS-dependent JNK and p38 MAPK signalling, while knockdown of salusin-β suppressed these effects. Conclusion:Our findings indicate that salusin-β can promote inflammation and apoptosis via ROS-dependent JNK and p38 MAPK signalling in HG-induced HRECs and could be a therapeutic target for DR.

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Salusin-β mediates tubular cell apoptosis in acute kidney injury: Involvement of the PKC/ROS signaling pathway

Cited by 44 publications

References 90 publications

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

Polysulfide and Hydrogen Sulfide Ameliorate Cisplatin-Induced Nephrotoxicity and Renal Inflammation through Persulfidating STAT3 and IKKβ

Polysulfide-mediated sulfhydration of SIRT1 prevents diabetic nephropathy by suppressing phosphorylation and acetylation of p65 NF-κB and STAT3

Salusin-β Mediates High Glucose-Induced Inflammation and Apoptosis in Retinal Capillary Endothelial Cells via a ROS-Dependent Pathway in Diabetic Retinopathy

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