Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway

Xiao, Jing; Zhang, Xiaoli; Fu, Chensheng; Han, Rui; Chen, Weijun; Lu, Yijun; Ye, Zhibin

doi:10.3892/ijmm.2015.2148

Cited by 127 publications

(122 citation statements)

References 51 publications

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“…XO inhibition had no significant effect on the level of urine sodium (Supplemental Table 2). Uric acid increases kidney fibrosis and inflammation, in part, through upregulation of fibronectin and TLR4 expression [17]. Therefore, we examined expression of fibronectin and TLR4 in kidney tissue.…”

Section: Resultsmentioning

confidence: 99%

“…We also observed that consumption of a WD was associated with increased renal tissue TLR4, and that this process was mitigated by allopurinol administration. Importantly, TLR4 is implicated in the kidney inflammatory responses and uric acid increases the expression of TLR4 in kidney [17]. Signaling through toll-like receptors activates dendritic cells and inflammatory cytokines to promote inflammation and fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

et al. 2017

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Objective Aortic vascular stiffness has been implicated in the development of cardiovascular disease (CVD) and chronic kidney disease (CKD) in obese individuals. However, the mechanism promoting these adverse effects are unclear. In this context, promotion of obesity through consumption of a western diet (WD) high in fat and fructose leads to excess circulating uric acid. There is accumulating data implicating elevated uric acid in the promotion of CVD and CKD. Accordingly, we hypothesized that xanthine oxidase inhibition with allopurinol would prevent a rise in vascular stiffness and proteinuria in a translationally relevant model of WD-induced obesity. Materials/Methods Four-week-old C57BL6/J male mice were fed a WD with excess fat (46%) and fructose (17.5%) with or without allopurinol (125mg/L in drinking water) for 16 weeks. Aortic endothelial and extracellular matrix/vascular smooth muscle stiffness was evaluated by atomic force microscopy. Aortic XO activity, 3-nitrotyrosine and aortic endothelial sodium channel (EnNaC) expression were evaluated along with aortic expression of inflammatory markers. In the kidney, expression of toll like receptor 4 (TLR4) and fibronectin were assessed along with evaluation of proteinuria. Results XO inhibition significantly attenuated WD-induced increases in plasma uric acid, vascular XO activity and oxidative stress, in concert with reductions in proteinuria. Further, XO inhibition prevented WD-induced increases in aortic EnNaC expression and associated endothelial and subendothelial stiffness. XO inhibition also reduced vascular pro-inflammatory and maladaptive immune responses induced by consumption of a WD. XO inhibition also decreased WD-induced increases in renal TLR4 and fibronectin that associated proteinuria. Conclusions Consumption of a WD leads to elevations in plasma uric acid, increased vascular XO activity, oxidative stress, vascular stiffness, and proteinuria all of which are attenuated with allopurinol administration.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

et al. 2017

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“…2007; Xiao et al. 2015) and therefore, can be important targets of several TLR4 ligands in the kidney. LPS is a well-established and studied TLR4 ligand, and is found in increased levels among CKD patients (McIntyre et al.…”

Section: Discussionmentioning

confidence: 99%

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

et al. 2015

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Chronic kidney disease (CKD) is associated with persistent low-grade inflammation and immunosuppression. In this study we tested the role of Toll-like receptor 4, the main receptor for endotoxin (LPS), in a mouse model of renal fibrosis and in a model of progressive CKD that better resembles the human disease. C3HeJ (TLR4 mutant) mice have a missense point mutation in the TLR4 gene, rendering the receptor nonfunctional. In a model of renal fibrosis after folic acid injection, TLR4 mutant mice developed less interstititial fibrosis in comparison to wild-type (WT) mice. Furthermore, 4 weeks after 5/6 nephrectomy with continuous low-dose angiotensin II infusion, C3HeOuJ (TLR4 WT) mice developed progressive CKD with albuminuria, increased serum levels of BUN and creatinine, glomerulosclerosis, and interstitial fibrosis, whereas TLR4 mutant mice were significantly protected from CKD progression. TLR4 WT mice also developed low-grade systemic inflammation, splenocyte apoptosis and increased expression of the immune inhibitory receptor PD-1 in the spleen, which were not observed in TLR4 mutant mice. In vitro, endotoxin (LPS) directly upregulated NLRP3 inflammasome expression in renal epithelial cells via TLR4. In summary, TLR4 contributes to renal fibrosis and CKD progression, at least in part, via inflammasome activation in renal epithelial cells, and may also participate in the dysregulated immune response that is associated with CKD.

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“…In this regard, it has been shown that when UA increases in a cell, there is an activation of NADPH oxidase in the kidney which increases oxidative stress and various pro-inflammatory and vasoactive mediators that lead to renal vasoconstriction, glomerular hypertension and eventually tubulointerstitial fibrosis and glomerular sclerosis [23]. In addition, both soluble and crystalized UA can also induce inflammasome activation and apoptosis in proximal tubule cells [24,25]. Therefore, it is possible that the primary protective effect of reducing UA levels is to preclude the activation of such prooxidant and proinflammatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Kidney Injury from Recurrent Heat Stress and Rhabdomyolysis: Protective Role of Allopurinol and Sodium Bicarbonate

et al. 2018

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Background: Heat stress and rhabdomyolysis are major risk factors for the occurrence of repeated acute kidney injury in workers exposed to heat and strenuous work. These episodes, in turn, may progress to chronic kidney disease. Objective: The purpose of this study was to test the effect of allopurinol (AP) and sodium bicarbonate on the kidney injury induced by recurrent heat stress dehydration with concomitant repeated episodes of rhabdomyolysis. Methods: The model consisted of heat stress exposure (1 h, 37°C) plus rhabdomyolysis (R) induced by repetitive IM injections of glycerol (7.5 mL/kg BW days) in the rat. In addition, to replicate the human situation, uricase was inhibited (oxonic acid [OA] 750 mg/K/d) to increase uric acid (UA) levels. Additional groups were treated either with AP 150 mg/L, n = 10, bicarbonate (BC; 160 mM, n = 10), or both (AP + BC, n = 10) in drinking water. We also included 2 control groups consisting of normal controls (N-Ref, n = 5) and uricase-inhibited rats (OA, n = 5) that were not exposed to heat or muscle injury. Groups were studied for 35 days. Results: Uricase-inhibited rats exposed to heat and rhabdomyolysis developed pathway and increased intrarenal oxidative stress and inflammasome activation. Kidney injury could be largely prevented by AP, and also BC, although the treatments were not synergistic. Conclusion: Increased levels of UA may play an important role in the renal alterations induced by heat stress and continuous episodes of rhabdomyolysis. Therefore, treatments aimed to reduce hyperuricemia may help to decrease the renal burden in these conditions. Clinical trials are suggested to test whether this is also true in humans.

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Soluble uric acid increases NALP3 inflammasome and interleukin-1β expression in human primary renal proximal tubule epithelial cells through the Toll-like receptor 4-mediated pathway

Cited by 127 publications

References 51 publications

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

Kidney Injury from Recurrent Heat Stress and Rhabdomyolysis: Protective Role of Allopurinol and Sodium Bicarbonate

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