The Role of the NLRP3 Inflammasome in Mediating Glomerular and Tubular Injury in Diabetic Nephropathy (original) (raw)
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European Journal of Pharmacology, 2020
Diabetes mellitus is an increasingly prevalent disease around the globe. The epidemic of diabetes mellitus and its complications pretenses the foremost health threat globally. Diabetic nephropathy is the notable complication in diabetes, leading to end-stage renal disease (ESRD) and premature death. Abundant experimental evidence indicates that oxidative stress and inflammation are the important mediators in diabetic kidney diseases and interlinked with various signal transduction molecular mechanisms. Inflammasomes are the critical components of innate immunity and are recognized as a critical mediator of inflammation and autoimmune disorders. NODlike receptor protein 3 (NLRP3) inflammasome is the well-characterized protein and it exhibits the sterile inflammation through the regulation of pro-inflammatory cytokines interleukin (IL)-1β and IL-18 production in tissues. In recent years, the role of NLRP3 inflammasome in the pathophysiology of diabetic kidney diseases in both clinical and experimental studies has generated great interest. In the current review, we focused on and discussed the role of NLRP3 inflammasome in diabetic nephropathy. A literature review was performed using online databases namely, PubMed, Scopus, Google Scholar and Web of science to explore the possible pharmacological interventions that blunt the NLRP3 inflammasome-caspase-1-IL-1β/IL-18 axis and shown to have a beneficial effect in diabetic kidney diseases. This review describes the inhibition of NLRP3 inflammasome activation as a promising therapeutic target for drug discovery in future.
The Role of Inflammasome-Dependent and Inflammasome-Independent NLRP3 in the Kidney
Cells, 2019
Cytoplasmic nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) forms an inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC) and pro-caspase-1, which is followed by the cleavage of pro-caspase-1 to active caspase-1 and ultimately the activation of IL-1β and IL-18 and induction of pyroptosis in immune cells. NLRP3 activation in kidney diseases aggravates inflammation and subsequent fibrosis, and this effect is abrogated by genetic or pharmacologic deletion of NLRP3. Inflammasome-dependent NLRP3 mediates the progression of kidney diseases by escalating the inflammatory response in immune cells and the cross-talk between immune cells and renal nonimmune cells. However, recent studies have suggested that NLRP3 has several inflammasome-independent functions in the kidney. Inflammasome-independent NLRP3 regulates apoptosis in tubular epithelial cells by interacting with mitochondria and mediating mitochondrial reactive oxygen species pro...
Nutrients
Diabetes mellitus is a metabolic disease largely due to lifestyle and nutritional imbalance, resulting in insulin resistance, hyperglycemia and vascular complications. Diabetic kidney disease (DKD) is a major cause of end-stage renal failure contributing to morbidity and mortality worldwide. Therapeutic options to prevent or reverse DKD progression are limited. Endothelial and glomerular filtration barrier (GFB) dysfunction and sterile inflammation are associated with DKD. Neutrophil extracellular traps (NETs), originally identified as an innate immune mechanism to combat infection, have been implicated in sterile inflammatory responses in non-communicable diseases. However, the contribution of NETs in DKD remains unknown. Here, we show that biomarkers of NETs are increased in diabetic mice and diabetic patients and that these changes correlate with DKD severity. Mechanistically, NETs promote NLRP3 inflammasome activation and glomerular endothelial dysfunction under high glucose str...
Clinical Science, 2022
Activation of nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3 (NLRP3) inflammasome has been reported in diabetic complications including diabetic kidney disease (DKD). However, it remains unknown if NLRP3 inhibition is renoprotective in a clinically relevant interventional approach with established DKD. We therefore examined the effect of the NLRP3-specific inhibitor MCC950 in streptozotocin-induced diabetic mice to measure the impact of NLRP3 inhibition on renal inflammation and associated pathology in DKD. We identified an adverse effect of MCC950 on renal pathology in diabetic animals. Indeed, MCC950-treated diabetic animals showed increased renal inflammation and macrophage infiltration in association with enhanced oxidative stress as well as increased mesangial expansion and glomerulosclerosis when compared with vehicle-treated diabetic animals. Inhibition of the inflammasome by MCC950 in diabetic mice led to renal up-regulation of markers of i...
NLRP3 Inflammasome Activation in Dialyzed Chronic Kidney Disease Patients
PloS one, 2015
To assess whether NLR pyrin domain-containing protein 3 (NLRP3) inflammasome, a multiprotein complex that mediates the activation of caspase-1 (CASP-1) and pro-inflammatory cytokines IL-18 and IL-1β, could be involved in the chronic inflammatory state observed in chronic kidney disease patients undergoing hemodialysis treatment (CKD-HD), we employed several biomolecular techniques including RT-PCR, western blot, FACS analysis, confocal microscopy and microarray. Interestingly, peripheral blood mononuclear cells from 15 CKD-HD patients showed higher mRNA levels of NLRP3, CASP-1, ASC, IL-1β, IL-18 and P2X7receptor compared to 15 healthy subjects. Western blotting analysis confirmed the above results. In particular, active forms of CASP-1, IL1-β and IL-18 resulted significantly up-regulated in CKD-HD versus controls. Additionally, elevated mitochondrial ROS level, colocalization of NLRP3/ASC/mitochondria in peripheral blood mononuclear cells from CKD-HD patients and down-regulation of ...
IUBMB Life, 2017
Diabetic nephropathy (DN) is one of the major causes of endstage renal disease. Nod-like receptors nucleotide-binding domain and leucine-rich repeat pyrin-3 domain (NLRP3) inflammasome displays a considerable role in the chronic inflammatory state observed in diabetic patients. Urinary heat shock protein 72 (uHSP72) is a sensitive and specific biomarker for the early detection of acute kidney injury. The aim of this study was to evaluate NLRP3 relative gene expression, its correlation with inflammatory and oxidative stress markers, and to assess the value of uHSP72 in the early detection of DN in type 2 diabetic patients with different degrees of DN. Forty-five type 2 diabetic patients: 15 normoalbuminuric, 15 microalbuminuric, 15 macroalbuminuric, in addition to 15 healthy controls were enrolled in this study. Clinical examination and routine laboratory investigations were performed. NLRP3 mRNA expression was assessed by real time polymerase chain reaction. Serum 8-hydroxy-2 0deoxyguanosine (8-OHdG), interleukin 1b (IL-1b), and uHSP72 levels were estimated by enzyme-linked immunosorbent assay. Serum chitotriosidase (CHIT1) activity was examined. NLRP3 mRNA relative expression, serum levels of 8-OHdG, IL-1b, and uHSP72, in addition to CHIT 1 activity were significantly increased in the macroalbuminuric patient group as compared to control and the other two diabetic groups. Also, a significant positive correlation was documented between the previously mentioned parameters and urinary albumin/ creatinine ratio, serum creatinine, and HbA1c. Multiple linear regression analysis using urinary albumin/creatinine ratio as dependent variable confirmed that uHSP72 and NLRP3 mRNA relative expression were the independent predictors of DN (b were 0.432 and 0.448 respectively, P < 0.001). Receiver operating characteristic analyses revealed that both NLRP3 mRNA relative expression and uHSP72 levels were useful biomarkers discriminating DN patients from patients with type 2 diabetes mellitus (AUC were 0.957 and 0.983, respectively). uHSP72 may be considered as a novel potential Abbreviations: CHIT1, chitotriosidase; HSP, heat shock protein; NLRP3, nod-like receptors nucleotide-binding domain and leucine-rich repeat pyrin-3 domain; 8-OHdG, 8-hydroxy-2 0-deoxyguanosine
NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy
Scientific Reports, 2017
We have previously showed that IL-1β is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.
Inflammasome-Independent NLRP3 Augments TGF-β Signaling in Kidney Epithelium
The Journal of Immunology, 2012
Tubulointerstitial inflammation and fibrosis are strongly associated with the outcome of chronic kidney disease. We recently demonstrated that the NOD-like receptor, pyrin domain containing-3 (NLRP3) contributes to renal inflammation, injury, and fibrosis following unilateral ureteric obstruction in mice. NLRP3 expression in renal tubular epithelial cells (TECs) was found to be an important component of experimental disease pathogenesis, although the biology of NLRP3 in epithelial cells is unknown. In human and mouse primary renal TECs, NLRP3 expression was increased in response to TGF-β1 stimulation and associated with epithelial–mesenchymal transition (EMT) and the expression of α-smooth muscle actin (αSMA) and matrix metalloproteinase (MMP) 9. TGF-β1–induced EMT and the induction of MMP-9 and αSMA were significantly decreased in mouse Nlrp3−/− renal TECs, suggesting a role for Nlrp3 in TGF-β–dependent signaling. Although apoptosis-associated speck-like protein containing a CARD d...
Kidney International, 2013
Tissue remodeling in kidney disease involves sterile inflammation, because tissue necrosis, in acute kidney injury, produces endogenous agonists to innate pattern recognition receptors that trigger innate immunity. In chronic kidney disease, however, a functional role of such pattern recognition receptors is questionable. Here we summarize and discuss the current evidence on a potential contribution of canonical and non-canonical pattern recognition receptor signaling in chronic kidney disease.