Tacrolimus ameliorates tubulointerstitial inflammation in diabetic nephropathy via inhibiting the NFATc1/TRPC6 pathway

Zhang, Shumin; Wang, Huafen; Liu, Yifei; Yang, Wenxia; Liu, Jialu; Han, Yuzhang; Liu, Yu; Liu, Fuyou; Sun, Lin; Xiao, Li

doi:10.1111/jcmm.15562

Cited by 14 publications

(15 citation statements)

References 49 publications

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“…A total of 38 transcription factor genes based on 166 DEGs between renal tubulointerstitial tissues of DN patients and normal controls were predicted via UCSC_TFBS. Certain genes such as CEBP and NFAT were observed significantly changed, which corresponded with our earlier researches [ 10 , 30 ]. As reported, downregulated CCAAT/enhancer binding protein β (C/EBP-β) in db/db mice was proven to induce activated SOCS3/STAT3 signaling pathway, and consequently promote diabetic tubulointerstitial inflammation [ 30 ].…”

Section: Discussionsupporting

confidence: 89%

“…Certain transcription factors (TFs) have been demonstrated to play an important role in these pathologies [ 6 ]. Clinical data has showed positive correlations between the transcription factors in tubular epithelial cells and DN progression, such as zinc-finger transcription factor snail homolog 1(Snai1) [ 7 ], X-box binding protein 1(XBP1) [ 8 ], hypoxia-inducible factor-1α(HIF-1α) [ 9 ], and nuclear factor of activated T cells 1(NFATc1) [ 10 ]. With in vivo studies, myocardin-related transcription factor A (MRTF-A) can promote transcription of type I and II collagen in an epigenetic manner [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Yin Yang 1 (YY1) has been shown to accelerate renal fibrosis in db/db mice by upregulating α-SMA expression and epithelial-mesenchymal transition (EMT) [ 14 ]. In addition, our previous studies have also demonstrated that Rap1b ameliorates diabetic tubular injury [ 15 ], and the inhibition of NFATc1/TRPC6 signaling mitigates diabetic tubulointerstitial inflammation with in vivo and in vitro study [ 10 ]. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial injury remain unclear.…”

Section: Introductionmentioning

confidence: 99%

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Identification of transcription factors related to diabetic tubulointerstitial injury

et al. 2023

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Background Diabetic nephropathy (DN) is a main cause of chronic renal failure. Despite decades of extensive study, the molecular mechanisms underlying diabetic tubulointerstitial injury remain unclear. We aim to identify key transcription factor genes involved in diabetic tubulointerstitial injury. Methods A microarray dataset (GSE30122) from Gene Expression Omnibus (GEO) was downloaded. A total of 38 transcription factor genes based on 166 differentially expressed genes (DEGs) were identified by UCSC_TFBS. Results The regulatory network showed connections between the top 10 transcription factors and their target DEGs. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of targeted DEGs indicated that extracellular space, extracellular exosome, cell surface and complement and coagulation cascades were most significantly enriched. Utilizing Nephroseq v5 online platform, the mRNA expression pattern analysis of transcription factor genes demonstrated that mRNA expression of CDC5, CEBPA, FAC1, HFH1, IRF1, NFE2 and TGIF1 increased in renal tubulointerstitium of DN patients compared with normal controls while that of CEBPB and FOXO4 decreased in renal tubulointerstitium of DN patients compared with normal controls. Correlation analysis between mRNA expression of transcription factor genes in renal tubulointerstitium and clinical features showed that AP1, BACH1, CDC5, FAC1, FOXD1, FOXJ2, FOXO1, FOXO4, HFH1, IRF1, POU3F2, SOX5, SOX9, RSRFC4, S8 and TGIF1 may be related to diabetic tubulointerstitial injury. Conclusions (1) CDC5, FAC1, FOXO4, HFH1, IRF1 and TGIF1 may be key transcription factor genes. (2)Transcription factors involved in diabetic tubulointerstitial injury may become prospective targets for diagnosis and treatment of DN.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of transcription factors related to diabetic tubulointerstitial injury

et al. 2023

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“…Inflammation may play a crucial role in the pathophysiology of DN, as evidence is mounting [23][24][25]. Hyperglycemia can stimulate the secretion of inflammatory cytokines, induce apoptosis, and generate numerous reactive oxygen species, resulting in injury to renal tubular epithelial cells [26], renal [27], mesangial cells [28,29], and podocytes [30].…”

Section: Discussionmentioning

confidence: 99%

lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

Yang

Song

Wang

et al. 2022

Journal of Immunology Research

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Objective. The long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) are closely associated with the pathogenesis of diabetic nephropathy (DN). But a complete mechanism for MALAT1 in DN has yet to be identified. This study investigated the effect of MALAT1 on DN through the regulation of miR-15b-5p/TLR4 signaling. Method. Renal tissues were collected from DN patients. Human renal tubular epithelial cells (HK-2) were used as a model of DN induced by high glucose (HG). We then measured the viability, apoptosis, and inflammatory cytokine levels of HK-2 cells using the corresponding assays. Following transfections of si-MALAT1, si-MALAT1+miR-15b-5p inhibitor, or si-MALAT1+vector TLR4 into HG-stimulated HK-2 cells, cell viability, apoptosis, and inflammatory cytokines were again measured. Furthermore, dual-luciferase reporter assay validated the interactions of MALAT1/miR-15b-5p and miR-15b-5p/TLR4. In addition, the interaction between MALAT1 and miR-15b-5p was investigated by RNA immunoprecipitation (RIP). Results. A significant upregulation of MALAT1 was observed in DN kidney tissues, as well as in HG-stimulated HK-2 cells. MALAT1 knockdown attenuates the inhibition of cell viability, apoptosis, and inflammatory response induced by HG in HK-2 cells. Moreover, a miR-15b-5p inhibitor or TLR4 overexpression reversed the above effects induced by MALAT1 knockdown. Conclusion. These results indicate that reduced MALAT1 ameliorates HG-stimulated HK-2 cell damage through an inhibition of the miR-15b-5p/TLR4 axis. MALAT1 may serve as a biomarker and potential therapeutic target for DN.

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“…Persistent hyperlipidemia and hyperglycemia can lead to vascular complications in the kidneys, heart, brain, eyes, and other primary organs (Domingueti et al, 2016; Jiang et al, 2020). Diabetic nephropathy, one of the most severe diabetic complications, can lead to extremely severe diseases and seriously affect human health and quality of life (Zhang et al, 2020). Moreover, about 20% to 40% of diabetic patients are also suffering from DN worldwide (Li, Hou, et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Chrysin improves diabetic nephropathy by regulating the AMPK ‐mediated lipid metabolism in HFD / STZ ‐induced DN mice

Zhou

Tao

et al. 2022

Journal of Food Biochemistry

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Diabetic nephropathy (DN) is a highly prevalent and severe diabetic complication. It is urgent to explore high efficiency and minor side effects therapy for DN. Chrysin is a natural flavonoid with various biological activities found in honey and propolis, and has considerable potential to improve DN. The study was designed to explore the effects and the specific underlying mechanism of chrysin for DN in high‐fat‐diet (HFD) and streptozotocin (STZ) induced DN mice. Firstly, the study revealed that chrysin effectively improved obesity, insulin resistance (IR), renal function, and pathological injury in DN mice. Secondly, the study found that chrysin improved the key indices and markers of lipid accumulation, oxidative stress, and inflammation which are closely related to the development or progression of DN. Moreover, chrysin markedly modulated lipid metabolism by regulating Adenosine 5′ monophosphate‐activated protein kinase (AMPK) and essential downstream proteins. Furthermore, AMPK inhibitor (Dorsomorphin) intervention partially suppressed the positive effects of chrysin on all testing indicators, indicating that activated AMPK is crucial for chrysin action on DN. The present study demonstrated that chrysin may improve DN by regulating lipid metabolism, and activated AMPK plays a critical role in the regulation of chrysin. Practical applications The study verified the positive effects of chrysin on obesity, insulin resistance, kidney injury, renal function, lipid accumulation, inflammation, and oxidative stress, which are closely related to the development or progression of diabetic nephropathy (DN). Moreover, we explored that chrysin improves DN by regulating AMPK‐mediated lipid metabolism. Furthermore, the AMPK inhibitor was used to confirm that activated AMPK plays a critical role in the effects of chrysin. These results could offer a full explanation and a potential option for adjuvant therapy of DN diabetes with chrysin.

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Tacrolimus ameliorates tubulointerstitial inflammation in diabetic nephropathy via inhibiting the NFATc1/TRPC6 pathway

Cited by 14 publications

References 49 publications

Identification of transcription factors related to diabetic tubulointerstitial injury

Identification of transcription factors related to diabetic tubulointerstitial injury

lncRNA MALAT1 Promotes Diabetic Nephropathy Progression via miR-15b-5p/TLR4 Signaling Axis

Chrysin improves diabetic nephropathy by regulating the AMPK ‐mediated lipid metabolism in HFD / STZ ‐induced DN mice

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