Carnosine alleviates podocyte injury in diabetic nephropathy by targeting caspase-1-mediated pyroptosis

Zhu, Wei; Li, Yuanyuan; Zeng, Han-xu; Liu, Xue-Qi; Sun, Yuting; Jiang, Ling; Xia, Lingling; Wu, Yuangang

doi:10.1016/j.intimp.2021.108236

Cited by 31 publications

(30 citation statements)

References 35 publications

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“…For instance, Caspase-11/4 and GSDMD-mediated pyroptosis were activated and involved in podocyte loss in high-fat diet/STZ-induced diabetic mice [5] . Caspase-1-mediated pyroptosis induced albuminuria, histopathological lesions and renal inflammation [10] . Our data indicated that the expression of pyroptosis-related genes NLRP3, caspase-1 and GSDMD was strikingly upregulated and the secretion of IL-1β and IL-18 in the serum was dramatically increased in diabetic mice.…”

Section: Discussionmentioning

confidence: 98%

“…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] . Moreover, Caspase-1 and GSDMD expressions were increased in renal biopsy tissue of patients with DN [9,10] . These studies indicated that pyroptosis was tightly implicated in DN progression.…”

Section: Introductionmentioning

confidence: 96%

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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: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 96%

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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“…The pathways to activate inflammasome include abnormal autophagy, abnormal production of mitochondrial ROS, and some metal state imbalance [ 44 ]. As mentioned earlier, phagolysosome disorders can also activate the NLRP3 inflammasome [ 45 , 46 ]. Gao et al showed that Schisandrin A suppressed pyroptosis by inhibiting NLRP3 inflammasome in THP-1 cells [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Schisandrin A from Schisandra chinensis Attenuates Ferroptosis and NLRP3 Inflammasome-Mediated Pyroptosis in Diabetic Nephropathy through Mitochondrial Damage by AdipoR1 Ubiquitination

Wang

Sui

et al. 2022

Oxidative Medicine and Cellular Longevity

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Schisandra chinensis, as a Chinese functional food, is rich in unsaturated fatty acids, minerals, vitamins, and proteins. Hence, this study was intended to elucidate the effects and biological mechanism of Schisandrin A from Schisandra chinensis in DN. C57BL/6 mice were fed with a high-fat diet and then injected with streptozotocin (STZ). Human renal glomerular endothelial cells were stimulated with 20 mmol/L d-glucose for DN model. Schisandrin A presented acute kidney injury in mice of DN. Schisandrin A reduced oxidative stress and inflammation in model of DN. Schisandrin A reduced high glucose-induced ferroptosis and reactive oxygen species (ROS-)-mediated pyroptosis by mitochondrial damage in model of DN. Schisandrin A directly targeted AdipoR1 protein and reduced LPS+ATP-induced AdipoR1 ubiquitination in vitro model. Schisandrin A activated AdipoR1/AMPK signaling pathway and suppressed TXNIP/NLRP3 signaling pathway in vivo and in vitro model of DN. Conclusively, our study revealed that Schisandrin A from Schisandra chinensis attenuates ferroptosis and NLRP3 inflammasome-mediated pyroptosis in DN by AdipoR1/AMPK-ROS/mitochondrial damage. Schisandrin A is a possible therapeutic option for DN or other diabetes.

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“…As an inhibitor of caspase-1, Vx-765 can improve the dysfunction of renal tubular epithelial cells in DN and regulate pyroptosis without affecting blood glucose levels or body weight ( Wen et al, 2022 ). Other studies have shown that carnosine can inhibit HG-induced podocyte pyroptosis through its target caspase-1 ( Zhu et al, 2021 ). Additionally, Sodium butyrate (NaB) can also inhibit pyroptosis by inhibiting caspase1/GSDMD axis in HG induced glomerular endothelial cells (GECs) ( Gu et al, 2019 ).…”

Section: Pyroptosis and Drugs In Diabetic Nephropathymentioning

confidence: 99%

NLRP3-mediated pyroptosis in diabetic nephropathy

Wan

Pan

et al. 2022

Front. Pharmacol.

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Diabetic nephropathy (DN) is the main cause of end-stage renal disease (ESRD), which is characterized by a series of abnormal changes such as glomerulosclerosis, podocyte loss, renal tubular atrophy and excessive deposition of extracellular matrix. Simultaneously, the occurrence of inflammatory reaction can promote the aggravation of DN-induced kidney injury. The most important processes in the canonical inflammasome pathway are inflammasome activation and membrane pore formation mediated by gasdermin family. Converging studies shows that pyroptosis can occur in renal intrinsic cells and participate in the development of DN, and its activation mechanism involves a variety of signaling pathways. Meanwhile, the activation of the NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome can not only lead to the occurrence of inflammatory response, but also induce pyroptosis. In addition, a number of drugs targeting pyroptosis-associated proteins have been shown to have potential for treating DN. Consequently, the pathogenesis of pyroptosis and several possible activation pathways of NLRP3 inflammasome were reviewed, and the potential drugs used to treat pyroptosis in DN were summarized in this review. Although relevant studies are still not thorough and comprehensive, these findings still have certain reference value for the understanding, treatment and prognosis of DN.

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Carnosine alleviates podocyte injury in diabetic nephropathy by targeting caspase-1-mediated pyroptosis

Cited by 31 publications

References 35 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

Schisandrin A from Schisandra chinensis Attenuates Ferroptosis and NLRP3 Inflammasome-Mediated Pyroptosis in Diabetic Nephropathy through Mitochondrial Damage by AdipoR1 Ubiquitination

NLRP3-mediated pyroptosis in diabetic nephropathy

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