Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy

Ke, Guibao; Chen, Xueqin; Liao, Ruyi; Xu, Lixia; Zhang, Li; Zhang, Hong; Kuang, Su‐Juan; Du, Yue; Hu, Juan; Lian, Zhiwen; Dou, Caoshuai; Zhang, Qianmei; Zhao, Xingchen; Zhang, Fengxia; Zhu, Shuangshuang; Ma, Jianchao; Li, Zhuo; Li, Sijia; He, Chaosheng; Chen, Xia; Wen, Yingzhen; Feng, Zhonglin; Zheng, Minghao; Lin, Tzu Chen; Li, Ruizhao; Li, Bohou; Dong, Wei; Chen, Yuanhan; Wang, Wenjian; Ye, Zhiming; Deng, Chunyu; Xiao, Houqin; Xiao, Jie; Liang, Xinling; Shi, Wei; Liu, Shuangxin

doi:10.1016/j.kint.2021.04.036

Cited by 34 publications

(19 citation statements)

References 44 publications

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“…Podocyte damage occurs in the early stage of DN, which causes proteinuria and accelerates the development of DN [ 33 ]. Nephrin and podocin are two main podocyte cytoskeleton proteins, which jointly maintain the normal morphology and function of podocytes, thus maintaining the normal filtration barrier function of the glomerulus [ 34 ]. Therefore, the stability of nephrin and podocin proteins is vital to renal function.…”

Section: Discussionmentioning

confidence: 99%

Trametenolic Acid Ameliorates the Progression of Diabetic Nephropathy in db/db Mice via Nrf2/HO-1 and NF-κB-Mediated Pathways

Duan

Tian

Feng

et al. 2022

Journal of Immunology Research

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Diabetic nephropathy (DN) is a fatal complication of diabetes and the main cause of end-stage renal disease. Due to the suboptimal effects of current treatments, there is an urgent need to develop new therapeutic strategies for DN. Trametenolic acid (TA), a lanostane-type tetracyclic triterpenoid, is one of the main active ingredients extracted from the natural product Inonotus obliquus. Our study was aimed at clarifying the potential protective effects of TA on DN and its underlying mechanism. In this research, C57BLKS/db (db/db) mice were used as the spontaneous DN model, and TA (10 mg/kg/d) was intraperitoneally injected for 4 consecutive weeks. Ratio of right kidney weight/body weight was calculated, and the contents of serum creatinine (Scr), blood urea nitrogen (BUN), and urine albumin were detected. The activities of superoxide dismutase (SOD) and catalase (CAT) and the contents of reductive glutathione (GSH) and malondialdehyde (MDA) were measured. The histopathological changes of renal tissues were observed by hematoxylin and eosin (HE), periodic acid-Schiff (PAS), and Masson staining. The protein expressions of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase-1 (NQO-1), nuclear factor kappa B (NF-κB), proinflammation cytokine tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), Nephrin, and Podocin were detected by western blot assay. Immunohistochemistry was utilized to detect expressions of collagen III (COL-III) and fibronectin (FN). Our results showed that TA administration significantly reduced the ratio of right kidney weight/body weight, BUN, Scr, and urine albumin levels and alleviated the histopathological changes of DN mice. Moreover, TA administration remarkably increased GSH content and SOD and CAT activities and decreased MDA content. Western blot assay demonstrated that TA activated Nrf2 signaling and increased the expression of downstream antioxidant enzymes HO-1 and NQO-1. Further studies illustrated that NF-κB signaling was inhibited, and downstream proinflammation cytokine expressions of TNF-α, IL-6, and IL-1β were also downregulated. In addition, we also found that TA administration significantly increased the expression of nephrin and podocin proteins and reduced the protein expression of COL-III and FN. These findings suggested that TA exhibited a renoprotective effect by ameliorating oxidative stress and inflammation via Nrf2/HO-1 and NF-κB signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Trametenolic Acid Ameliorates the Progression of Diabetic Nephropathy in db/db Mice via Nrf2/HO-1 and NF-κB-Mediated Pathways

Duan

Tian

Feng

et al. 2022

Journal of Immunology Research

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“…Excessive activation of NF-κB can lead to apoptosis of vascular endothelial cells. At the same time, NF-κB as an inflammatory mediator can activate a series of inflammatory reactions in the kidney, thereby aggravating kidney damage and accelerating the occurrence and development of DKD ( Tóbon-Velasco et al, 2014 ; Yang et al, 2019 ; Ke et al, 2021 ). MAPK8 is a member of the MAPK family.…”

Section: Discussionmentioning

confidence: 99%

Mechanism of Tripterygium wilfordii Hook.F.- Trichosanthes kirilowii Maxim decoction in treatment of diabetic kidney disease based on network pharmacology and molecular docking

Peng²,

Wan³

et al. 2022

Front. Pharmacol.

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Background: Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease. The effective treatment of DKD would rely on the incorporation of a multi-disciplinary. Studies have shown that Tripterygium wilfordii Hook.F. and Trichosanthes kirilowii Maxim have remarkable curative effects in treating DKD, but their combination mechanism has not been fully elucidated.Methods: We explored the mechanism of Tripterygium wilfordii Hook.F.-Trichosanthes kirilowii Maxim decoction (Leigongteng-Tianhuafen Decoction,LTD) in the treatment of DKD by network pharmacology and molecular docking. The main active components and action targets of LTD were collected from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The speculative targets of DKD were obtained from GeneCards, DisGeNET, and Online Mendelian Inheritance in Man (OMIM) databases. Then, an herb-component-target network was constructed based on the above analyses. The biological function of targets was subsequently investigated, and a protein-protein interaction (PPI) network was constructed to identify hub targets of DKD. The gene ontology (GO) function enrichment analysis and kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis were performed by RStudio. Finally, molecular docking was performed by AutoDock Vina and PyMOL software to explore the interaction between compounds and targets. Furthermore, the DKD model of human renal tubular cells (HK-2) induced by high glucose (HG) was selected, and the predicted results were verified by western blot analysis and immunofluorescence.Results: A total of 31 active components of LTD were screened out, and 196 targets were identified based on the TCMSP database. A total of 3,481 DKD related targets were obtained based on GeneCards, DisGeNET, and OMIM databases. GO function enrichment analysis included 2,143, 50, and 167 GO terms for biological processes (BPs), cellular composition (CCs), and molecular functions (MFs), respectively. The top 10 enrichment items of BP annotations included response to lipopolysaccharide, response to molecule of bacterial origin, response to extracellular stimulus, etc. CC was mainly enriched in membrane raft, membrane microdomain, plasma membrane raft, etc. The MF of LTD analysis on DKD was predominately involved in nuclear receptor activity, ligand-activated transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor binding, etc. The involvement signaling pathway of LTD in the treatment of DKD included AGE-RAGE signaling pathway in diabetic complications, IL-17 signaling pathway, insulin resistance, TNF signaling pathway, etc. Molecular docking results showed that kaempferol, triptolide, nobiletin, and schottenol had a strong binding ability to PTGS2 and RELA. Furthermore, the in vitro experiments confirmed that LTD effectively decreased the expression of PTGS2, NF-κB, JNK, and AKT in the HG-induced DKD model.Conclusion: The findings of this study revealed that the therapeutic efficacy of LTD on DKD might be achieved by decreasing the expression of PTGS2, NF-κB, JNK, and AKT, which might improve insulin resistance, inflammation, and oxidative stress. These findings can provide ideas and supply potential therapeutic targets for DKD.

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“…In summary, we believe that OPG/RANK/RANKL system may be involved in the pathogenesis of DKD-one of the common microvascular complications in type 2 diabetes. In the latest study, 22 it was confirmed that RANK made important contribution to the development of DKD, which was mainly manifested in the obvious increase of RANK expression in DKD mice, consistently with the occurrence of albuminuria and renal dysfunction. In contrast, the absence of RANK protected against glomerular basement membrane thickening and mesangial dilatation.…”

mentioning

confidence: 83%

Elevated Serum Osteoprotegerin is Associated with Reduced Risks of Albuminuria and CKD Progression in Patients with Type 2 Diabetes

Lou¹,

Liu²,

Wu³

et al. 2022

DMSO

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To analyze the correlation between serum osteoprotegerin (OPG) level and chronic kidney disease (CKD) at different CKD stages in patients with type 2 diabetes. Methods: All subjects were hospitalized patients with type 2 diabetes. Medical history collection, physical examinations, and blood and urine samples testing were performed. Stages of CKD (G1-5) were defined by eGFR, groups of persistent albuminuria (normal, microalbuminuria and massive albuminuria) were divided by UACR, and categories of CKD progression risks (low, moderate and high or very high risk) were recommended by the Kidney Disease: Improving Global Outcomes (KDIGO). Serum OPG level was determined by enzyme-linked immunosorbent assay in the central laboratory. Results: Four hundred and eighty-four patients were included in the study. The average level of OPG of all subjects was 941.30 (547.53-1332.62) pg/mL. The levels of OPG decreased gradually with the aggravation of albuminuria (P = 0.007, P for trend =0.003) and CKD progression (P = 0.001, P for trend =0.001). No differences were found between OPG levels and stages of CKD (P = 0.31). After the adjustment, each 100 pg/mL increase in OPG levels could reduce the risk of massive albuminuria (OR 0.92, 95% CI 0.86-0.99, P = 0.02) and the high or very high risk of CKD progression (OR 0.94, 95% CI 0.89-0.99, P = 0.04) by multivariate logistic regression analysis. No correlations were found between OPG and stages of CKD. Conclusion:In patients with type 2 diabetes, elevated serum osteoprotegerin is associated with albuminuria and the risk of CKD progression, and may delay the progression of CKD.

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Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy

Cited by 34 publications

References 44 publications

Trametenolic Acid Ameliorates the Progression of Diabetic Nephropathy in db/db Mice via Nrf2/HO-1 and NF-κB-Mediated Pathways

Trametenolic Acid Ameliorates the Progression of Diabetic Nephropathy in db/db Mice via Nrf2/HO-1 and NF-κB-Mediated Pathways

Mechanism of Tripterygium wilfordii Hook.F.- Trichosanthes kirilowii Maxim decoction in treatment of diabetic kidney disease based on network pharmacology and molecular docking

Elevated Serum Osteoprotegerin is Associated with Reduced Risks of Albuminuria and CKD Progression in Patients with Type 2 Diabetes

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