Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy

Wu, Ming; Yang, Zhifen; Zhang, Chengyu; Shi, Yu; Han, Weiping; Song, Shan; Lin, Ming Tsan; Du, Chunyang; Shi, Yonghong

doi:10.1016/j.metabol.2021.154748

Cited by 97 publications

(70 citation statements)

References 50 publications

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“…Previous reports in DN showed that the increase of triglycerides, inducing lipotoxicity and later kidney damage is related to fibrosis onset [ 272 ]. In this regard, the activation of NLRP3 also promotes lipid accumulation, as was recently demonstrated by Wu et al [ 273 ]. These authors reported that diabetic mice increased lipid deposition via IL-1β/ROS/NF-κB p65, triggering NLRP3 priming, which induces the upregulation of sterol regulatory element-binding protein 1 (SREBP1) and 2 (SREBP2).…”

Section: Inflammasome Components In Ckdmentioning

confidence: 53%

“…The latter proteins are involved in lipid biosynthesis. Moreover, the ATP-binding cassette transporter (ABCA1), a protein implicated in the transport of phospholipids, cholesterol, and other metabolites from cells to lipid-depleted HDL apolipoproteins, decreases [ 273 , 274 ]. The knockout of NLPR3 avoids inflammation and fibrosis by reducing lipid deposition, suggesting the involvement of NLPR3 to induce lipid accumulation [ 273 ].…”

Section: Inflammasome Components In Ckdmentioning

confidence: 99%

“…Moreover, the ATP-binding cassette transporter (ABCA1), a protein implicated in the transport of phospholipids, cholesterol, and other metabolites from cells to lipid-depleted HDL apolipoproteins, decreases [ 273 , 274 ]. The knockout of NLPR3 avoids inflammation and fibrosis by reducing lipid deposition, suggesting the involvement of NLPR3 to induce lipid accumulation [ 273 ]. Moreover, lipid deposition via inflammasome activation has been attributed to the upregulation of IL-1β, which stimulates the cluster of differentiation 36 (CD36) to mediate fatty acid uptake [ 275 , 276 ].…”

Section: Inflammasome Components In Ckdmentioning

confidence: 99%

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Involvement of Inflammasome Components in Kidney Disease

et al. 2022

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Inflammasomes are multiprotein complexes with an important role in the innate immune response. Canonical activation of inflammasomes results in caspase-1 activation and maturation of cytokines interleukin-1β and -18. These cytokines can elicit their effects through receptor activation, both locally within a certain tissue and systemically. Animal models of kidney diseases have shown inflammasome involvement in inflammation, pyroptosis and fibrosis. In particular, the inflammasome component nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) and related canonical mechanisms have been investigated. However, it has become increasingly clear that other inflammasome components are also of importance in kidney disease. Moreover, it is becoming obvious that the range of molecular interaction partners of inflammasome components in kidney diseases is wide. This review provides insights into these current areas of research, with special emphasis on the interaction of inflammasome components and redox signalling, endoplasmic reticulum stress, and mitochondrial function. We present our findings separately for acute kidney injury and chronic kidney disease. As we strictly divided the results into preclinical and clinical data, this review enables comparison of results from those complementary research specialities. However, it also reveals that knowledge gaps exist, especially in clinical acute kidney injury inflammasome research. Furthermore, patient comorbidities and treatments seem important drivers of inflammasome component alterations in human kidney disease.

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Section: Inflammasome Components In Ckdmentioning

confidence: 53%

Section: Inflammasome Components In Ckdmentioning

confidence: 99%

Section: Inflammasome Components In Ckdmentioning

confidence: 99%

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Involvement of Inflammasome Components in Kidney Disease

et al. 2022

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“…Moreover, a previous study reported that activation of the Nod-like receptor protein 3 (NLRP3) inflammasome was observed in HG-induced podocytes and db/db mice. The inhibition of NLRP3 inflammasome activation is a potential target for DN treatment (Wu et al, 2021). To elucidate the role of NLRP3 inflammasome in fisetin treatment, we analyzed the levels of NLRP3, cleaved caspase-1, and IL-1β.…”

Section: Fisetin Activates Cdkn1b and P70s6k-mediated Autophagy In Hg-induced Podocyte Injurymentioning

confidence: 99%

Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome

Dong

Jia

et al. 2022

Front. Pharmacol.

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Diabetic nephropathy (DN) is one of the primary complications of diabetes. Fisetin is a flavonoid polyphenol that is present in several vegetables and fruits. The present study investigated the mechanisms of fisetin in DN-induced podocyte injury both in vitro and in vivo. The results revealed that fisetin ameliorated high glucose (HG)-induced podocyte injury and streptozotocin (STZ)-induced DN in mice. CDKN1B mRNA expression in the glomeruli of patients with DN decreased based on the Nephroseq dataset, and fisetin reversed CDKN1B expression at mRNA and protein levels in a dose-dependent manner in podocytes and mice kidney tissues. Furthermore, fisetin suppressed the phosphorylation of P70S6K, a downstream target of CDKN1B, activated autophagosome formation, and inhibited Nod-like receptor protein 3 (NLRP3) inflammasomes. Interfering CDKN1B reduced the protective effects of fisetin against high glucose-induced podocyte injury. Molecular docking results revealed a potential interaction between fisetin and CDKN1B. In summary, the present study revealed that fisetin alleviated high glucose-induced podocyte injury and STZ-induced DN in mice by restoring autophagy-mediated CDKN1B/P70S6K pathway and inhibiting NLRP3 inflammasome.

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“…Including interleukin-1 β (IL-1β), IL-6, tumor necrosis factor -α (TNF-α), and monocyte chemotactic protein 1(MCP-1), which aggravate kidney injury [11,12] . Nod-like receptor protein-3 (NLRP3) in ammasome is an assembled molecular complex consisting of NLRP3, apoptosis-associated speck-like protein containing CARD (ASC), and cysteinyl aspartate speci c proteinase (caspase-1) [13,14] .…”

Section: Introductionmentioning

confidence: 99%

Oridonin Attenuates Diabetes‑Induced Renal Fibrosis via Inhibition of the TXNIP/NLRP3 and NF‑κB Pathway in Rats

Huang

Zhang

et al. 2021

Preprint

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Background: Oxidative stress and its induced inflammation are important pathological processes of diabetic nephropathy (DN). Oridonin, a component isolated from Rabdosia rubescens, possesses remarkable anti-inflammatory, immunoregulatory properties, it is also a newly reported NLRP3 inhibitor. However, the renoprotective effects of Oridonin and the underlying molecular mechanisms have not been explored in DN. We hypothesized that Oridonin could reduce NLRP3 pathway and ameliorate diabetes‑induced renal fibrosis.Methods: We used STZ-induced diabetic rats combined high-fat diet to establish a T2DM animal model, and then treated with Oridonin (10, 20 mg/kg/day) for two weeks. Kidney function and renal fibrosis were assessed. In addition, the expression of inflammatory factors and fibrotic markers were analyzed by western blot.Results: Oridonin treatment preserved kidney function and markedly limited the renal fibrosis size in diabetic rats. The renal fibrotic markers were inhibited in the 10 mg/kg/day group and 20 mg/kg/day group compared to the T2DM group. Moreover, the expression levels of TXNIP/NLRP3 and NF‑κB pathway were decreased in the Oridonin treatment group compared to non-treated group. Conclusions: The NLRP3-inflammasome inhibitor Oridonin reduces renal fibrosis and preserves kidney function in T2DM rat model, which indicates potential therapeutic effect of Oridonin on DN.

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Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy

Cited by 97 publications

References 50 publications

Involvement of Inflammasome Components in Kidney Disease

Involvement of Inflammasome Components in Kidney Disease

Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome

Oridonin Attenuates Diabetes‑Induced Renal Fibrosis via Inhibition of the TXNIP/NLRP3 and NF‑κB Pathway in Rats

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