Abstract
Mesangial cell (MC) proliferation is one of the important pathological features of obesity-associated nephropathy with unknown etiology. Excessive MC proliferation can cause glomerulosclerosis and renal function loss. Thus, targeting MC proliferation may be a potential strategy for the treatment of obesity-associated kidney disease. The present study was undertaken to investigate the role of celastrol in MC proliferation induced by ox-LDL, as well as the potential mechanisms. Following ox-LDL treatment, MC proliferation was induced and the NLRP3 inflammasome was activated, as evidenced by increased NLRP3 levels, caspase 1 activity, and IL-18 and IL-1β release. Significantly, NLRP3 siRNAs inhibited MC proliferation and delayed cell cycle progression, as indicated by the cell cycle assay and the expression of cyclin A2 and cyclin D1. Given the anti-inflammatory effect of celastrol, we pretreated MCs with celastrol before ox-LDL treatment. As expected, celastrol pretreatment strikingly inhibited NLRP3 inflammasome activation and MC proliferation triggered by ox-LDL. In summary, celastrol potently blocked ox-LDL-induced MC proliferation, possibly by inhibiting NLRP3 inflammasome activation. These findings also suggest that celastrol may be a potential drug for treating proliferative glomerular diseases related to obesity and lipid disorders.
Highlights
Considerable evidence has shown that obesity-related metabolic syndrome (MetS) is a major risk factor for glomerulopathy[1,2,3,4,5,6]
Lipid metabolism disorders are commonly associated with hyperlipidemia and the glomerular accumulation of atherogenic lipoproteins, of which the oxidatively modified low-density lipoprotein is a compelling contributor to glomerular mesangial proliferation, inflammation and extracellular matrix (ECM) expansion, which leads to glomerulosclerosis and nephron loss[7,8,9,10,11,12]
Ox-LDL-induced mesangial cell (MC) proliferation To confirm that oxidatively modified low-density lipoprotein (ox-LDL) treatment can induce MC
Summary
Considerable evidence has shown that obesity-related metabolic syndrome (MetS) is a major risk factor for glomerulopathy[1,2,3,4,5,6]. Lipid metabolism disorders are commonly associated with hyperlipidemia and the glomerular accumulation of atherogenic lipoproteins, of which the oxidatively modified low-density lipoprotein (ox-LDL) is a compelling contributor to glomerular mesangial proliferation, inflammation and extracellular matrix (ECM) expansion, which leads to glomerulosclerosis and nephron loss[7,8,9,10,11,12]. In kidney MCs, recent research has demonstrated that activation of the NLRP3 inflammasome contributes to high-glucose-induced rat mesangial cell inflammation and immunoglomerulonephritis[11,16,17]. The role of the NLRP3 inflammasome in lipidrelated mesangial cell proliferation remains unclear. Celastrol is a triterpene extracted from the traditional Chinese medicinal plant Tripterygium wilfordii Hook F and is listed by the journal Cell as one of the five traditional medicinal compounds most likely to be developed
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