Activation of COX-2/mPGES-1/PGE2 Cascade via NLRP3 Inflammasome Contributes to Albumin-Induced Proximal Tubule Cell Injury

Abstract

Background/Aims: The activation of NOD-like receptor family, pyrin domain containing3 (NLRP3) inflammasome has been shown to be positively correlated with the severity of proteinuria in chronic kidney disease (CKD) patients. Prostaglandin E2 (PGE2), an important inflammatory mediator, is also involved in various kidney injuries. The aim of the present study was to investigate the involvement of NLRP3 inflammasome and PGE2 synthetic pathway in albumin-induced renal tubular injury. Methods: Murine proximal tubular cells (mPTCs) were treated with albumin to induce cell injury. NLRP3 siRNA and specific COX-2 inhibitor NS398 were used to define their roles in mediating albumin-induced mPTC injury or the activation of COX-2/mPGES-1/PGE2 cascade. Results: In mPCTs, inhibition of NLRP3 by a small interfering RNA (siRNA) blocked albumin-induced kidney injury molecule 1 (KIM-1) upregulation, inflammatory response, and cell apoptosis. Albumin markedly activated cyclooxygenase-2 (COX-2)/ microsomal prostaglandin E synthase-1 (mPGES-1)/PGE2 pathway in this cell line, an effect largely abolished by NLRP3 silencing at both mRNA and protein levels. More interestingly, blockade of COX-2 using a specific COX-2 inhibitor NS398 markedly inhibited the upregulation of KIM-1 and inflammatory cytokines, and attenuated cell apoptosis in line with blunted PGE2 release following albumin treatment. Conclusions: The findings suggest that COX-2/mPGES-1/PGE2 axis could be activated by albumin in the proximal tubular cells via a NLRP3 inflammasome-mediated mechanism and could thus contribute to proteinuria-related renal tubular cell injury.

Plasma-borne indicators of inflammasome activity in Parkinson’s disease patients

“…Although not statistically significant in our study, we observed a lower proportion of patients with elevated NLRP3 (p = 0.11) among ibuprofen users, an NSAID well associated with a reduced risk of PD 10 . These data are consistent with previous reports suggesting certain NSAIDs are capable of inhibiting NLRP3 95 and studies reporting mechanistic links between one major NSAID target, COX2, and the NLRP3 inflammasome 96,97 . Based on the frequent reporting of "overthe-counter" anti-inflammatory drug use by PD patients, our data indicating elevated NLRP3 in PD is likely an underrepresentation of the actual relationship between circulating pyroptosis-related proteins and PD.…”

Renal fibrosis: Primacy of the proximal tubule

“…Proximal tubules exposed to albumin also augmented production of profibrotic TGF-β and its type II receptor as well as accumulation of ECM components collagen IV, laminin, and fibronectin in vitro[127–129]. More recent data has linked protein reabsorption and lysosomal rupture with stimulation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in the proximal tubule[130, 131]. Albumin exposure to the proximal tubule also impairs autophagy in vitro by activating mammalian target of rapamycin (mTOR), a known autophagy inhibitor.…”

NLRP3 inflammasome inhibitor MCC950 attenuates primary dysmenorrhea in mice via the NF-κB/COX-2/PG pathway

“…It has also been reported that NF-κB induces the activation of COX-2 genes in primary dysmenorrhea [44], and some studies have shown that the NLRP3 inflammasome upregulates NF-κB activation and promotes COX-2 expression [45]. Moreover, it has been reported that NLRP3 inflammasomes could be responsible for mediating the albumin effect on activating the COX-2/mPGES-1/PGE2 cascade, but the role of NF-kB in this case is not known [12]. The effect of NLRP3 on COX-2 is not clear, but we think that NLRP3 regulates COX-2 through the NF-κB pathway, and the NLRP3 inflammasome might be involved in the pathological progression of PD through the NF-κB/COX-2/PG pathway.…”

“…The assembly of the NLRP3 inflammasome as stimulated by NLRP3 irritants triggers proteolytic cleavage of dormant procaspase-1 into active caspase-1, which converts the cytokines pro-IL-1β and pro-IL-18 into mature and biologically active IL-1β and IL-18, respectively, leading to a cascade of deleterious inflammation [10]. Moreover, there is increasing evidence indicating that the NLRP3 inflammasome plays a regulatory role in the expression of COX-2 via the NF-κB pathway [11,12]. Our previous studies have found that the NLRP3 inflammasome can be activated and expressed in PD, and effective traditional electroacupuncture therapy to treat PD is associated with the inhibition of NLRP3 inflammasome activation [13].…”