A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation
CongXiao Zhang,*,1,2 XinWang Zhu,*,1 LuLu Li,1 TianKui Ma,1 Mai Shi,1 Ying Yang,1 QiuLing Fan11Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Blood Purification Center, Shenyang the 4th Hospital of People, Shenyang 11...
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Dove Medical Press
2019
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oai:doaj.org-article:83590df8cfef47f1a8c6e154af6ab4ff2021-12-02T01:07:30ZA small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation1178-7007https://doaj.org/article/83590df8cfef47f1a8c6e154af6ab4ff2019-08-01T00:00:00Zhttps://www.dovepress.com/a-small-molecule-inhibitor-mcc950-ameliorates-kidney-injury-in-diabeti-peer-reviewed-article-DMSOhttps://doaj.org/toc/1178-7007CongXiao Zhang,*,1,2 XinWang Zhu,*,1 LuLu Li,1 TianKui Ma,1 Mai Shi,1 Ying Yang,1 QiuLing Fan11Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Blood Purification Center, Shenyang the 4th Hospital of People, Shenyang 110031, People’s Republic of China*These authors contributed equally to this workBackground: Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation.Methods: To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic db/db mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1β expression in the renal cortices of db/db mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1β expression in the glomerular mesangial cells were measured.Results: The NLRP3 inflammasome was activated in db/db mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1β pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1β in db/db mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in db/db mice. MCC950 increased the expression of podocin in db/db mice, and decreased the expression of TGF-β1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of db/db mice and HG-induced mesangial cells.Conclusion: MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in db/db mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1β pathway, which may be a potential therapeutic strategy to prevent the progression of DN.Keywords: diabetic nephropathy, MCC950, NLRP3 inflammasome, db/db mice, mesangial cellsZhang CZhu XLi LMa TShi MYang YFan QDove Medical Pressarticlediabetic nephropathyMCC950NLRP3 inflammasomedb/db micemesangial cellsSpecialties of internal medicineRC581-951ENDiabetes, Metabolic Syndrome and Obesity: Targets and Therapy, Vol Volume 12, Pp 1297-1309 (2019) |
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diabetic nephropathy MCC950 NLRP3 inflammasome db/db mice mesangial cells Specialties of internal medicine RC581-951 |
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diabetic nephropathy MCC950 NLRP3 inflammasome db/db mice mesangial cells Specialties of internal medicine RC581-951 Zhang C Zhu X Li L Ma T Shi M Yang Y Fan Q A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation |
| description |
CongXiao Zhang,*,1,2 XinWang Zhu,*,1 LuLu Li,1 TianKui Ma,1 Mai Shi,1 Ying Yang,1 QiuLing Fan11Department of Nephrology, The First Hospital of China Medical University, Shenyang 110001, People’s Republic of China; 2Blood Purification Center, Shenyang the 4th Hospital of People, Shenyang 110031, People’s Republic of China*These authors contributed equally to this workBackground: Diabetic nephropathy (DN) is a lethal diabetic microvascular complication characterized by chronic low-grade inflammation. The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome is implicated in the progression of DN. MCC950 is a selective and potent inhibitor of NLRP3; however, its efficacy in DN requires further investigation.Methods: To investigate the efficacy of MCC950 in DN, eight-week-old type 2 diabetic db/db mice received injections of MCC950 intraperitoneally (10 mg/kg) twice per week for 12 weeks. Urinary albumin-to-creatinine ratio (ACR) and neutrophil gelatinase-associated lipocalin (NGAL), renal function, pathological changes, markers of podocyte and fibrosis and NLPR3/caspase-1/IL-1β expression in the renal cortices of db/db mice were evaluated. High-glucose (HG)-treated rat glomerular mesangial cells were treated with various concentrations of MCC950 for 48 hrs. Markers of fibrosis and NLPR3/caspase-1/IL-1β expression in the glomerular mesangial cells were measured.Results: The NLRP3 inflammasome was activated in db/db mice and HG-induced mesangial cells by upregulating NLRP3/caspase-1/IL-1β pathway. Inhibition of the NLRP3 inflammasome with MCC950 reduced the production of active caspase-1 and active IL-1β in db/db mice and HG-induced mesangial cells. MCC950 reduced serum creatinine, urinary ACR and NGAL, attenuated mesangial expansion with increased matrix and tubular dilatation, alleviated thickened glomerular basement membrane (GBM) and foot process fusion without affecting body weight and blood glucose levels in db/db mice. MCC950 increased the expression of podocin in db/db mice, and decreased the expression of TGF-β1, fibronectin, collagen I and α-smooth muscle actin (α-SMA) in renal cortices of db/db mice and HG-induced mesangial cells.Conclusion: MCC950 ameliorated renal function, thickened GBM, podocyte injury and renal fibrosis in db/db mice, and decreased the production of fibrosis markers in HG-induced mesangial cells. MCC950 effectively ameliorated diabetic kidney injury by inhibiting NLRP3/caspase-1/IL-1β pathway, which may be a potential therapeutic strategy to prevent the progression of DN.Keywords: diabetic nephropathy, MCC950, NLRP3 inflammasome, db/db mice, mesangial cells |
| format |
article |
| author |
Zhang C Zhu X Li L Ma T Shi M Yang Y Fan Q |
| author_facet |
Zhang C Zhu X Li L Ma T Shi M Yang Y Fan Q |
| author_sort |
Zhang C |
| title |
A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation |
| title_short |
A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation |
| title_full |
A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation |
| title_fullStr |
A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation |
| title_full_unstemmed |
A small molecule inhibitor MCC950 ameliorates kidney injury in diabetic nephropathy by inhibiting NLRP3 inflammasome activation |
| title_sort |
small molecule inhibitor mcc950 ameliorates kidney injury in diabetic nephropathy by inhibiting nlrp3 inflammasome activation |
| publisher |
Dove Medical Press |
| publishDate |
2019 |
| url |
https://doaj.org/article/83590df8cfef47f1a8c6e154af6ab4ff |
| work_keys_str_mv |
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