Activation of the NLRP3 Inflammasome in Association with Calcium Oxalate Crystal Induced Reactive Oxygen Species in Kidneys

Joshi, Sunil; Wang, Wei; Peck, Ammon B.; Khan, Saeed R.

doi:10.1016/j.juro.2014.11.093

Cited by 76 publications

(57 citation statements)

References 29 publications

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“…The role of reactive oxygen species in mediation of NLRP3 activation is the most plausible [39,40]. Consistent with this, we showed that renal mRNA expression of NOX1 and NOX2 (gp91 phox , p47 phox , and p67 phox ) was increased in doxorubicin nephropathy, and that this upregulation of gp91 phox , p47 phox , and p67 phox mRNA was effectively blocked by sitagliptin treatment.…”

Section: Discussionsupporting

confidence: 86%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

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Background/Aims: Dipeptidyl peptidase-4 (DPP4) inhibitors are known to have a protective effect on diabetic kidney disease, possibly via reduction of oxidative stress and inflammation in the kidney. However, whether these potential mechanisms play a role in non-diabetic proteinuric kidney diseases is not clear. Methods: Two different animal experiments were carried out using sitagliptin and linagliptin for DPP4 inhibition. In each experiment, male Sprague-Dawley rats were uninephrectomized and randomly divided into vehicle-treated and doxorubicin-treated rats, with or without DPP4 inhibition. Administration of a DPP4 inhibitor was performed daily by oral gavage over six weeks. Results: A single intravenous injection of doxorubicin resulted in hypertension and remarkable proteinuria. Linagliptin, but not sitagliptin, lowered systolic blood pressure in rats with doxorubicin nephropathy. By contrast, sitagliptin ameliorated tubulointerstitial injury, inflammatory cell infiltration, and interstitial fibrosis in rat kidneys with doxorubicin nephropathy. Quantitative polymerase chain reaction analysis revealed that mRNA expression of NLRP3, caspase-1, ASC, and IL-1β was remarkably increased in rat kidneys with doxorubicin nephropathy, and that this upregulation of the major components of the NLRP3 inflammasome was effectively suppressed by treatment with either sitagliptin or linagliptin. Additionally, upregulation of IL-6 was reversed by linagliptin, but not by sitagliptin. On the other hand, sitagliptin, but not linagliptin, reversed the increase in mRNA expression of gp91^phox, p47^phox, and p67^phox in rat kidneys with doxorubicin nephropathy. Conclusion: NLRP3 inflammasome activation was shown in our rat model of doxorubicin nephropathy. DPP4 inhibitors can suppress the activity of NLRP3, with or without relieving NADPH oxidase 2-related oxidative stress.

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Section: Discussionsupporting

confidence: 86%

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Kim

Park

et al. 2018

Kidney Blood Press Res

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“…TXNIP can directly bind to NLRP3 in a ROS sensitive manner. Previous studies have demonstrated that ROS caused high levels of TXNIP, thus causing NLRP3 activation [44], which subsequently lead to activation of caspase-1 and forming of IL-1β [12]. It is well accepted that enhanced IL-1β may play a deleterious role in angiogenesis and vascular repairing [13].…”

Section: Discussionmentioning

confidence: 99%

PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

Deng¹,

Han²,

Zheng³

et al. 2017

Cell Physiol Biochem

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Background: Impaired wound healing is a common complication of diabetes and is the leading cause of lower extremity amputation. Treatment with fenofibrate, a peroxisome proliferators–activated receptor α (PPARα) agonist, was associated with a lower risk of amputations, particularly minor amputations without known large-vessel diseases, probably through non-lipid mechanisms. The current study aimed to test our hypothesis that fenofibrate stimulates angiogenesis and restores endothelial precursor cell (EPC) function via inhibiting Nod-like receptor protein 3 (NLRP3) inflammasome in streptozotocin (STZ)-induced diabetic mice. Methods: Male C57BL/6 mice were randomly divided into three groups: control, STZ-induced diabetic mice and fenofibrate treated diabetic group. Wound closure was assessed by wound area and CD31 positive capillaries. Both the migration and tube formation capacities of EPCs were measured. Intracellular nitric oxide (NO) and superoxide (O₂^-) levels were determined. Activity of NLRP3 inflammasome in EPCs was assessed by measuring thioredoxin-interacting protein (TXNIP), NLRP3, and caspase-1 expression. Results: Compared with the untreated diabetic mice, wound closure and capillary densities were significantly increased in fenofibrate treated group. Fenofibrate treatment restored EPC function, increased NO production, and decreased O₂^- level in EPCs of diabetic mice. Furthermore, fenofibrate deregulated the activity of NLRP3 inflammasome by reducing TXNIP, NLRP3 and caspase-1 expression in EPCs of diabetic mice. In vitro, fenofibrate prevented high glucose induced EPC dysfunction, deregulated NLRP3 inflammasome activity. In addition, fenofibrate inhibited IL-1β expression caused by combination use of high glucose and lipopolysaccharide. Conclusion: Fenofibrate can accelerate wound healing in diabetic mice, which at least in part was mediated by improving the impaired EPC function via a NLRP3 inflammasome pathway, suggesting the significance of PPARα agonists in the treatment of diabetes.

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“…In addition, recruited blood monocytes could differentiate in situ into dendritic cells, which are not able to remove CaOx deposits and might further accelerate the kidney damage through CaOx-induced NLRP3 inflammasome activation and enhanced IL-1beta production. 29 The third scenario that could potentially prevent the macrophage-mediated removal of interstitial crystal deposits and promote accumulation of crystals and development of nidus would involve a lack of local inflammatory signals, i.e. chemokines such as CCL2 required for recruitment of blood monocytes.…”

Section: Discussionmentioning

confidence: 99%

Calcium Oxalate Stone Fragment and Crystal Phagocytosis by Human Macrophages

et al. 2016

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Purpose In murine and human hyperoxaluric conditions, macrophages can be seen surrounding renal calcium oxalate (CaOx) crystal deposits. We hypothesize that macrophages play a role in degrading and destroying these deposits and investigated inflammatory response and phagocytic mechanisms when macrophages are exposed to human kidney stones and inorganic crystals. Materials and Methods Human monocytes were differentiated into resting, fully-differentiated macrophages by treating with recombinant human M-CSF or GM-CSF for 6 days. After confirming phenotype by flow cytometry, macrophages were exposed for 20 hours to fragments of sterile human CaOx stones or CaOx crystals. Crystal uptake was determined, and supernatant cytokine and chemokine profiles were analyzed using antibody arrays. qRT-PCR was used to validate mRNA profile expression. Results Under direct-vision fluorescent microscopy, activated human macrophages were noted to surround both stone fragments and synthesized crystals and destroy them in a step-by-step process that involved clathrin-mediated endocytosis and phagocytosis. An inflammatory cascade was released by macrophages, including chemokines CCL2, CCL3, interleukin-1 receptor antagonist (IL-1ra), complement component C5/C5a and IL-8. The response patterns to stone and crystal material was dependent on macrophage phenotype and activation status. Conclusions In our in vitro study, macrophages differentiated with M-CSF displayed a greater ability to phagocytize crystal deposits than those treated with GM-CSF. Following clathrin-mediated endocytosis, macrophages released a number of cytokines crucial for inflammatory immune response, suggesting that tissue macrophages play an important role in preventing kidney stone disease by removing and digesting interstitial renal crystal deposits.

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Activation of the NLRP3 Inflammasome in Association with Calcium Oxalate Crystal Induced Reactive Oxygen Species in Kidneys

Cited by 76 publications

References 29 publications

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

Anti-Inflammatory Action of Sitagliptin and Linagliptin in Doxorubicin Nephropathy

PPARα Agonist Stimulated Angiogenesis by Improving Endothelial Precursor Cell Function Via a NLRP3 Inflammasome Pathway

Calcium Oxalate Stone Fragment and Crystal Phagocytosis by Human Macrophages

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