NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation

Li, Shu; Lin, Qisheng; Shao, Xinghua; Mou, Shan; Gu, Leyi; Wang, Ling; Zhang, Zhen; Shen, Jianxiao; Zhou, Yijun; Chen, Qi; Jin, Haijiao; Pang, Huihua; Ni, Zhaohui

doi:10.1016/j.yexcr.2019.07.001

Cited by 78 publications

(41 citation statements)

References 34 publications

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“…Kidney fibrosis is a common endpoint of various progressive kidney diseases such as DN, which leads to loss of nephrons and is characterized by the activation of fibroblasts, epithelial-to-mesenchymal transition, macrophage infiltration, and excessive ECM accumulation that may lead to the development of ESRD [5,6]. Inflammation plays a critical role in the initiation and progression of renal fibrosis [1,2,3]. We have recently demonstrated that an inflammatory process is induced in initial stages of DN with increased cytokines, chemokines, cell adhesion molecules, and growth factors in glomeruli and proximal tubules [18,19].…”

Section: Discussionmentioning

confidence: 99%

“…Diabetic nephropathy (DN) is considered a long-term diabetes mellitus complication with proteinuria, a progressive decline in renal function accompanied by glomerular and interstitial fibrosis. It is considered to be the leading cause of dysfunction in end-stage renal disease (ESRD) [1,2]. The fibrotic process is characterized by sustained inflammation, including inflammatory cell infiltration and secretion of cytokines, accumulation and imbalance of extracellular matrix (ECM), with degradation and activation of myofibroblasts [3,4,5].…”

Section: Introductionmentioning

confidence: 99%

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All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

et al. 2019

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Diabetic nephropathy (DN) involves damage associated to hyperglycemia and oxidative stress. Renal fibrosis is a major pathologic feature of DN. The aim of this study was to evaluate anti-fibrogenic and renoprotective effects of all-trans retinoic acid (ATRA) in isolated glomeruli and proximal tubules of diabetic rats. Diabetes was induced by single injection of streptozotocin (STZ, 60 mg/Kg). ATRA (1 mg/Kg) was administered daily by gavage, from days 3–21 after STZ injection. ATRA attenuated kidney injury through the reduction of proteinuria, renal hypertrophy, increase in natriuresis, as well as early markers of damage such as β2-microglobulin, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase-associated lipocalin (NGAL). The following parameters increased: macrophage infiltration, localization of alpha-smooth muscle actin (αSMA)-positive cells in renal tissue, and pro-fibrotic proteins such as transforming growth factor-β (TGF-β1), laminin beta 1 (LAM-β1), and collagens IV and I. Remarkably, ATRA treatment ameliorated these alterations and attenuated expression and nuclear translocation of Smad3, with increment of glomerular and tubular Smad7. The diabetic condition decreased expression of retinoic acid receptor alpha (RAR-α) through phosphorylation in serine residues mediated by the activation of c-Jun N-terminal kinase (JNK). ATRA administration restored the expression of RAR-α and inhibited direct interactions of JNK/RAR-α. ATRA prevented fibrogenesis through down-regulation of TGF-β1/Smad3 signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

et al. 2019

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“…25,26 MCC950, a type of thiourea compound, is a specific inhibitor of NLRP3 and has been once administered to hypertensive kidney and renal fibrosis induced by oxalate crystallization animal models. 45,46 The NLRP3 inhibition mechanism of MCC950 involves the binding of this compound to the Walker B motif of the NATCH domain and the prevention of hydrolysis, which decreases inflammasome packaging and activation. MCC950 can also change the conformation of NLRP3 24,47 and recognize the adenosine triphosphate motif of the NATCH domain to stop the packaging and activation of NLRP3 inflammasomes.…”

Section: F I G U R E 6 66pr and Mcc950 Compound Relieved The Damage Omentioning

confidence: 99%

NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions

Liu

Chen

Niu

et al. 2021

Clinical & Translational Med

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Background Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney function, and NLR family pyrin domain containing 3 (NLRP3) inflammasome was augmented in case of kidney injury. However, the detailed mechanism regarding whether NLRP3 inflammasome is involved in kidney function injury in AHTR is not fully understood yet. Methods Hemolysis models were established by vein injection with human blood plasma or mouse heme from destroyed red blood cells. The injured renal tubular epithelial cells (RTECs) were evaluated by tubular damage markers staining in hemolysis models and in primary RTECs in vitro. The activation of NLRP3 inflammasome in RTECs by hemes was investigated by Western blot, ELISA, scanning electron microscopy, immunofluorescent staining, flow cytometry, and hemolysis models. NLRP3 gene knockout mice were employed to confirm these observations in vitro and in vivo. The binding between a novel inhibitor (66PR) and NLRP3 was affirmed by molecule docking and co‐immunoprecipitation. The rescue of 66PR on kidney function impairment was explored in murine hemolysis models. Results We found that heme could activate NLRP3 inflammasome in RTECs to induce kidney function injury. NLRP3 gene knockout could prevent the damage of RTECs caused by hemes and recover kidney function in AHTR. Moreover, NLRP3 inflammasome chemical inhibitor, 66PR, could bind to NLRP3 protein and inhibit inflammasome activation in RTECs, which consequently relieved the injury of RTECs caused by hemes, and alleviated kidney function damage in the AHTR model. Conclusions Hemes could activate NLRP3 inflammasome in RTECs, and a novel NLRP3 inflammasome inhibitor named 66PR relieved kidney function damage in AHTR. Our findings provided a new possible strategy to treat kidney function failure in AHTR.

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“…Among the putative mechanisms that contribute to the pathogenesis of CKD, oxidative stress has been recognized as accelerating disease progression through cardiovascular complications, inflammation, fibrosis, and apoptosis, as well as through glomerular filtration barrier damage [21,36]. For example, the glomerulosclerosis process, which is associated with an increase in oxidative stress, is induced by both increased transforming growth factor β (TGFβ) expression and reduced nitric oxide production/activity, causing tubulointerstitial fibrosis and inducing tubular destruction [37][38][39].…”

Section: Oxidative Stress and Chronic Kidney Diseasementioning

confidence: 99%

Oxidative Imbalance and Kidney Damage: New Study Perspectives from Animal Models to Hospitalized Patients

2019

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Chronic kidney disease (CKD) is a major public health problem worldwide and affects both elderly and young subjects. Its main consequences include the loss of renal function, leading to end-stage renal disease, an increased risk of cardiovascular disease, a significant increase in morbidity and mortality, and a decrease in health-related quality of life. This review arose in significant part from work in the authors’ laboratory, complemented by literature data, and was based on a translational approach: we studied the role of many CKD risk factors, such as hypertension, obesity, and oxidative stress/inflammation. The aim was to identify new molecular mechanisms of kidney damage to prevent it through successful behavior modifications. For this purpose, in our studies, both human and animal models were used. In the animal models, we analyzed the mechanisms of renal damage induced by hypertension (spontaneously hypertensive rats) and obesity (cafeteria diet-fed rats), showing that redox disequilibrium in plasma and tissue is extremely important in renal alteration in terms of both oxidative damage (lipid peroxidation, altered expression antioxidant enzymes) and apoptotic pathway (intrinsic/extrinsic) activation. In hemodialysis patients, we explored the correlation between the global oxidative balance and both inflammatory markers and cardiovascular risk, showing a strong correlation between the oxidative index and the blood levels of C-reactive protein and previous cardiovascular events. This multilevel approach allowed us to individually and synergistically analyze some aspects of the complex pathogenic mechanisms of CKD in order to clarify the role of the new amplified risk factors for CKD and to prepare an effective personalized prevention plan by acting on both modifiable and nonmodifiable risk factors.

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NLRP3 inflammasome inhibition attenuates cisplatin-induced renal fibrosis by decreasing oxidative stress and inflammation

Cited by 78 publications

References 34 publications

All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

All-Trans Retinoic Acid Attenuates Fibrotic Processes by Downregulating TGF-β1/Smad3 in Early Diabetic Nephropathy

NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions

Oxidative Imbalance and Kidney Damage: New Study Perspectives from Animal Models to Hospitalized Patients

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