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Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy.
Metabolism. 2021 05; 118:154748.M

Abstract

BACKGROUND

Nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome is documented as a potent target for treating metabolic diseases and inflammatory disorders. Our recent work demonstrated that inhibition of NLRP3 inflammasome activation inhibits renal inflammation and fibrosis in diabetic nephropathy. This study was to investigate the effect of NLRP3 inflammasome on podocyte injury and the underlying mechanism in diabetic nephropathy.

METHODS

In vivo, db/db mice were treated with MCC950, a NLRP3 inflammasome specific inhibitor. NLRP3 knockout (NKO) mice were induced to diabetes by intraperitoneal injections of streptozotocin (STZ). We assessed renal function, albuminuria, podocyte injury and glomerular lipid accumulation in diabetic mice. In vitro, apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation and reactive oxygen species (ROS) generation were evaluated in podocytes interfered with NLRP3 siRNA or MCC950 under high glucose (HG) conditions. In addition, the effect and mechanism of IL-1β on lipid accumulation was explored in podocytes exposed to normal glucose (NG) or HG.

RESULTS

MCC950 treatment improved renal function, attenuated albuminuria, mesangial expansion, podocyte loss, as well as glomerular lipid accumulation in db/db mice. The diabetes-induced podocyte loss and glomerular lipid accumulation were reversed in NLRP3 knockout mice. The increased expression of sterol regulatory element-binding protein1 (SREBP1) and SREBP2, and decreased expression of ATP-binding cassette A1 (ABCA1) in podocytes were reversed by MCC950 treatment or NLRP3 knockout in diabetic mice. In vitro, NLRP3 siRNA or MCC950 treatment markedly inhibited HG-induced apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation, and mitochondrial ROS production in cultured podocytes. In addition, BAY11-7082 or tempol treatment inhibited HG-induced lipid accumulation in podocytes. Moreover, exposure of IL-1β to podocytes induced lipid accumulation, NF-κB p65 activation and mitochondrial ROS generation.

CONCLUSION

Inhibition of NLRP3 inflammasome protects against podocyte damage through suppression of lipid accumulation in diabetic nephropathy. IL-1β/ROS/NF-κB p65 mediates diabetes-associated lipid accumulation in podocytes. The suppression of NLRP3 inflammasome activation may be an effective therapeutic approach to diabetic nephropathy.

Authors+Show Affiliations

Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang 050017, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang 050017, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China.Department of Pathology, Hebei Medical University, Shijiazhuang 050017, China; Hebei Key Laboratory of Kidney Disease, Shijiazhuang 050017, China; Center of Metabolic Diseases and Cancer Research, Institute of Medical and Health Science, Hebei Medical University, Shijiazhuang 050017, China. Electronic address: yonghongshi@163.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

33675822

Citation

Wu, Ming, et al. "Inhibition of NLRP3 Inflammasome Ameliorates Podocyte Damage By Suppressing Lipid Accumulation in Diabetic Nephropathy." Metabolism: Clinical and Experimental, vol. 118, 2021, p. 154748.
Wu M, Yang Z, Zhang C, et al. Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. Metabolism. 2021;118:154748.
Wu, M., Yang, Z., Zhang, C., Shi, Y., Han, W., Song, S., Mu, L., Du, C., & Shi, Y. (2021). Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. Metabolism: Clinical and Experimental, 118, 154748. https://doi.org/10.1016/j.metabol.2021.154748
Wu M, et al. Inhibition of NLRP3 Inflammasome Ameliorates Podocyte Damage By Suppressing Lipid Accumulation in Diabetic Nephropathy. Metabolism. 2021;118:154748. PubMed PMID: 33675822.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of NLRP3 inflammasome ameliorates podocyte damage by suppressing lipid accumulation in diabetic nephropathy. AU - Wu,Ming, AU - Yang,Zhifen, AU - Zhang,Chengyu, AU - Shi,Yu, AU - Han,Weixia, AU - Song,Shan, AU - Mu,Lin, AU - Du,Chunyang, AU - Shi,Yonghong, Y1 - 2021/03/04/ PY - 2020/09/27/received PY - 2021/02/18/revised PY - 2021/02/27/accepted PY - 2021/3/7/pubmed PY - 2021/5/28/medline PY - 2021/3/6/entrez KW - Diabetic nephropathy KW - Lipid accumulation KW - NLRP3 inflammasome KW - Podocyte injury SP - 154748 EP - 154748 JF - Metabolism: clinical and experimental JO - Metabolism VL - 118 N2 - BACKGROUND: Nucleotide leukin-rich polypeptide 3 (NLRP3) inflammasome is documented as a potent target for treating metabolic diseases and inflammatory disorders. Our recent work demonstrated that inhibition of NLRP3 inflammasome activation inhibits renal inflammation and fibrosis in diabetic nephropathy. This study was to investigate the effect of NLRP3 inflammasome on podocyte injury and the underlying mechanism in diabetic nephropathy. METHODS: In vivo, db/db mice were treated with MCC950, a NLRP3 inflammasome specific inhibitor. NLRP3 knockout (NKO) mice were induced to diabetes by intraperitoneal injections of streptozotocin (STZ). We assessed renal function, albuminuria, podocyte injury and glomerular lipid accumulation in diabetic mice. In vitro, apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation and reactive oxygen species (ROS) generation were evaluated in podocytes interfered with NLRP3 siRNA or MCC950 under high glucose (HG) conditions. In addition, the effect and mechanism of IL-1β on lipid accumulation was explored in podocytes exposed to normal glucose (NG) or HG. RESULTS: MCC950 treatment improved renal function, attenuated albuminuria, mesangial expansion, podocyte loss, as well as glomerular lipid accumulation in db/db mice. The diabetes-induced podocyte loss and glomerular lipid accumulation were reversed in NLRP3 knockout mice. The increased expression of sterol regulatory element-binding protein1 (SREBP1) and SREBP2, and decreased expression of ATP-binding cassette A1 (ABCA1) in podocytes were reversed by MCC950 treatment or NLRP3 knockout in diabetic mice. In vitro, NLRP3 siRNA or MCC950 treatment markedly inhibited HG-induced apoptosis, cytoskeleton change, lipid accumulation, NF-κB p65 activation, and mitochondrial ROS production in cultured podocytes. In addition, BAY11-7082 or tempol treatment inhibited HG-induced lipid accumulation in podocytes. Moreover, exposure of IL-1β to podocytes induced lipid accumulation, NF-κB p65 activation and mitochondrial ROS generation. CONCLUSION: Inhibition of NLRP3 inflammasome protects against podocyte damage through suppression of lipid accumulation in diabetic nephropathy. IL-1β/ROS/NF-κB p65 mediates diabetes-associated lipid accumulation in podocytes. The suppression of NLRP3 inflammasome activation may be an effective therapeutic approach to diabetic nephropathy. SN - 1532-8600 UR - https://www.unboundmedicine.com/medline/citation/33675822/Inhibition_of_NLRP3_inflammasome_ameliorates_podocyte_damage_by_suppressing_lipid_accumulation_in_diabetic_nephropathy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0026-0495(21)00048-2 DB - PRIME DP - Unbound Medicine ER -