Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis

Han, Jianyong; Zuo, Zhenkui; Shi, Xiujie; Yage, Zhang; Peng, Zining; Xing, Yufeng; Pang, Xinxin

doi:10.1007/s10565-021-09622-z

Cited by 32 publications

(24 citation statements)

References 25 publications

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“…The expression of the NLRP3 inflammasome, cleaved Caspase-1 and GSDMD-N, and the secretion of IL-1β were increased in the kidneys of db/db mice and STZ-induced SD rats [6] . In addition, deletion of GSDMD reduced pyroptosis and improved kidney injury in both STZ-induced diabetic mice and high glucose-stimulated glomerular endothelial cells as well as renal tubular epithelial cells [7] . VX-765, a Caspase-1 inhibitor, decreased pyroptosisassociated protein expression and then suppressed inflammatory cell infiltration as well as tubulointerstitial fibrosis in diabetic animals [8] .…”

Section: Introductionmentioning

confidence: 94%

Syringaresinol attenuates kidney injury by inhibition of pyroptosis via activating the Nrf2 antioxidant pathway in diabetic nephropathy

Liu

Yang

et al. 2022

Preprint

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Background and Purpose: Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes that has limited treatment options. NLRP3-initiated pyroptosis is tightly implicated in DN progression. Mitochondrial ROS (mtROS) are a critical trigger of NLRP3 activation. Syringaresinol, a natural plant-derived polyphenolic compound, possesses strong antioxidant properties. However, whether syringaresinol provides renoprotection in DN remains unclear. Experimental Approach: The renoprotection effects of syringaresinol were investigated in streptozotocin-induced wild-type and Nrf2-KO mice. The underlying mechanism of syringaresinol on DN was assessed in diabetic renal tissues and high glucose-stimulated primary renal tubular epithelial cells as well as glomerular mesangial cells HBZY-1. Key Results: Syringaresinol treatment ameliorated renal structural and functional changes in streptozotocin-induced diabetic mice, including renal hypertrophy, fibrosis, mesangial expansion, glomerular basement membrane thickening, podocyte foot process effacement and albuminuria. Mechanistically, syringaresinol prevented the NLRP3/Caspase-1/GSDMD pyroptosis pathway and promoted Nrf2 expression and nuclear transfer in both diabetic renal tissues and high glucose-stimulated primary renal tubular epithelial cells as well as HBZY-1 cells. After that, the nuclear-transferred Nrf2 upregulated the antioxidant genes HO-1 and MnSOD, thereby effectively improving mitochondrial dysfunction and decreasing excess cytosolic ROS and mtROS. Most importantly, knockout of Nrf2 abolished the syringaresinol-mediated renoprotection and antioxidant effects and subsequent mtROS overproduction, resulting in the activation of NLRP3/Caspase-1/GSDMD signaling. Conclusion and Implications: Syringaresinol attenuated diabetic renal lesions by preventing the NLRP3/Caspase-1/GSDMD pyroptosis pathway in an Nrf2-dependent manner. This suggests that syringaresinol may represent promising therapeutic options for DN.

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Section: Introductionmentioning

confidence: 94%

Syringaresinol attenuates kidney injury by inhibition of pyroptosis via activating the Nrf2 antioxidant pathway in diabetic nephropathy

Liu

Yang

et al. 2022

Preprint

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“…Recent studies have demonstrated a pivotal role of NLRP3 inflammasome activation in endothelial barrier dysfunction by inducing pyroptosis and disruption of tight junctions [74][75][76][77]. In DM, hyperglycemia changes endothelial permeability by inducing endothelial cell pyroptosis in an NLRP3 inflammasomedependent manner, and inhibition of the NLRP3 inflammasome ameliorates endothelial barrier dysfunction [78,79]. In addition, increased formation and activation of the NLRP3 inflammasome complex, characterized by increased production of IL-1β and caspase-1, downregulate the expression levels of tight junction protein zonula occludens-1/2 (ZO-1/2) in coronary arterial endothelium of STZ-induced diabetic NLRP3+/+ C57BL/6J mice, leading to coronary arterial endothelium barrier integrity wreck and increased endothelial permeability, while NLRP3 deletion eliminates the destruction of the endothelial barrier and restores the expression of tight junction protein [32,33].…”

Section: Nlrp3 Inflammasome In Endothelial Barriermentioning

confidence: 99%

The Role of NLRP3 Inflammasome in Diabetic Cardiomyopathy and Its Therapeutic Implications

Ding

Song

et al. 2022

Oxidative Medicine and Cellular Longevity

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Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus (DM). However, the precise molecular mechanisms remain largely unclear, and it is still a challenging disease to diagnose and treat. The nucleotide-binding oligomerization domain and leucine-rich repeat pyrin 3 domain (NLRP3) inflammasome is a critical part of the innate immune system in the host to defend against endogenous danger and pathogenic microbial infections. Dysregulated NLRP3 inflammasome activation results in the overproduction of cytokines, primarily IL-1β and IL-18, and eventually, inflammatory cell death-pyroptosis. A series of studies have indicated that NLRP3 inflammasome activation participates in the development of DCM, and that corresponding interventions could mitigate disease progression. Accordingly, this narrative review is aimed at briefly summarizing the cell-specific role of the NLRP3 inflammasome in DCM and provides novel insights into developing DCM therapeutic strategies targeting the NLRP3 inflammasome.

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“…Cell type/animal model Effects Ac-YVAD-CMK [29,33] Caspase-1 inhibitor GECs [29] Reduce the expression of NLRP3, caspase-1, and IL-1β VX-765 [51] Immortalized mouse podocyte cell line [29,33] HBZY-1 [51] Sodium butyrate [29] Caspase-1-GSDMD, GECs Ameliorate caspase-1-GSDMD-IL-1β/IL-18 canonical pyroptosis pathway and NF-κB/IκB-α signaling pathway NF-κB/IκB-α Hirudin [30] IRF2-GSDMD GECs, RTECs, and BMDMs Inhibit IRF2-induced GSDMD MCC950 [32] NLRP3 inhibitor db/db mice and rat mesangial cells< H3 relaxin [73] P2X7R/NLRP3 HRMECs Attenuate P2X7R-mediated NLRP3 inflammasome activation and the expression of caspase-1, GSDMD, IL-1β, and IL-18…”

Section: Intervention Targetsmentioning

confidence: 99%

“…Our previous study showed that high glucose levels could induce pyroptosis in GECs, which was alleviated by a caspase-1 inhibitor or sodium butyrate [ 29 ]. Another study reported that hirudin ameliorated DN by inhibiting GSDMD-mediated pyroptosis in GECs [ 30 ].…”

Section: Pyroptosis In Diabetic Microvascular Diseasesmentioning

confidence: 99%

“…Moreover, circACTR2 regulates high glucose-induced pyroptosis, inflammation, and fibrosis in proximal tubular cells [ 59 ]. Specific inhibitors of pyroptosis in RTEC have not been well studied, and existing evidence suggests a potential function for an A1 adenosine receptor agonist [ 35 ] or hirudin [ 30 ]. In summary, the canonical pyroptosis pathway is associated with intrinsic damage to RTECs and plays an essential role in DN development.…”

Section: Pyroptosis In Diabetic Microvascular Diseasesmentioning

confidence: 99%

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Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications

Geng

Guo

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Pyroptosis is an inflammatory form of programmed cell death that is dependent on inflammatory caspases, leading to the cleavage of gasdermin D (GSDMD) and increased secretion of interleukin (IL)-1β and IL-18. Recent studies have reported that hyperglycemia-induced cellular stress stimulates pyroptosis, and different signaling pathways have been shown to play crucial roles in regulating pyroptosis. This review summarized and discussed the molecular mechanisms, regulation, and cellular effects of pyroptosis in diabetic microvascular complications, such as diabetic nephropathy, diabetic retinopathy, and diabetic cardiomyopathy. In addition, this review aimed to provide new insights into identifying better treatments for diabetic microvascular complications.

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Hirudin ameliorates diabetic nephropathy by inhibiting Gsdmd-mediated pyroptosis

Cited by 32 publications

References 25 publications

Syringaresinol attenuates kidney injury by inhibition of pyroptosis via activating the Nrf2 antioxidant pathway in diabetic nephropathy

Syringaresinol attenuates kidney injury by inhibition of pyroptosis via activating the Nrf2 antioxidant pathway in diabetic nephropathy

The Role of NLRP3 Inflammasome in Diabetic Cardiomyopathy and Its Therapeutic Implications

Targeting Pyroptosis: New Insights into the Treatment of Diabetic Microvascular Complications

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