NLRP3 Inflammasome Mediates Albumin-induced Renal Tubular Injury through Impaired Mitochondrial Function

Zhuang, Yibo; Ding, Guofu; Zhao, Min; Bai, Mei; Yang, Lu; Ni, Jiajia; Wang, Rong; Jia, Zhanjun; Huang, Songming; Zhang, Aihua

doi:10.1074/jbc.m114.578260

Cited by 71 publications

(67 citation statements)

References 38 publications

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“…Recent evidence demonstrated that the NLRP3 inflammasome played a detrimental role in kidney diseases [24-26]. Our previous study also showed that the NLRP3 inflammasome was involved in aldosterone-induced podocyte injury and 5/6 nephrectomy- related renal tubular damage [12, 13, 27]. In the present study, we found that Ang II activated the NLRP3 inflammasome in podocytes and that NLRP3 silencing attenuated the Ang II-induced podocyte apoptosis and loss of the podocyte-specific proteins nephrin and podocin.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of the NLRP3 inflammasome finally triggers the maturation of IL-1β and IL-18 via activated caspase-1 [10, 11]. Studies from our and other groups suggest that activation of the NLRP3 inflammasome is involved in renal tubular and podocyte injury induced by albuminuria or aldosterone [12-15]. However, the role of the NLRP3 inflammasome in Ang II-induced podocyte injury has not been defined.…”

Section: Introductionmentioning

confidence: 99%

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Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

et al. 2018

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Background: We previously reported that the NLRP3 inflammasome played an important role in mediating the podocyte injury induced by aldosterone. However, more studies on the role of the NLRP3 inflammasome in the pathogenesis of podocytopathy are still required. The present study was undertaken to study the role of the NLRP3 inflammasome in angiotensin II (Ang II)-induced podocyte injury, as well as the potential mechanisms. Methods: In this study, we used an Ang II infusion model in NLRP3^–/– mice. In cultured podocytes, we used siRNA to silence NLRP3; then we treated the podocytes with Ang II. Results: Following Ang II treatment, we found that the NLRP3 inflammasome was significantly activated in line with mitochondrial dysfunction in a dose- and time-dependent manner. Silencing NLRP3 by siRNA transfection ameliorated podocyte apoptosis, attenuated the loss of the podocyte proteins nephrin and podocin, and protected mitochondrial function. Ang II infusion activated the NLRP3 inflammasome, caused albuminuria, and induced podocyte damage, which was all blocked in the NLRP3^–/– mice. At the same time, NLRP3 deletion also ameliorated the mitochondrial dysfunction induced by Ang II infusion. However, the deletion of NLRP3 did not affect the Ang II hypertension. Conclusion: Taken together, these results demonstrate an important role of the NLRP3 inflammasome in mediating Ang II-induced podocyte injury and mitochondrial dysfunction, suggesting that the NLRP3 inflammasome might be an effective therapeutic target against podocytopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

et al. 2018

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“…Activation of the NLRP3 inflammasome may augment the inflammatory response, leading to subsequent cellular injury. Another report by us (22) demonstrated that genetic disruption of NLRP3, both in animals and in vitro in cells, markedly attenuated albumin-induced renal tubular cell injury, demonstrating a pathogenic role for the mitochondria/NLRP3 inflammasome axis in this pathological process.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury

Zhuang

Yasinta

et al. 2015

American Journal of Physiology-Renal Physiology

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“…[23][24][25] A large number of studies have shown that mitochondrial dysfunction plays an important role in the progression of renal disease including renal tubular injury, chronic kidney disease, and acute renal failure, which can lead to renal disease aggravation and progression. [26][27][28] More and more evidences suggested that the damage of mitochondrial morphological and function plays an important role in the development of DN. 29,30 Malik et al 31 found that mitochondrial DNA copy number of peripheral blood in patients with DN is significantly higher than the DM group without nephropathy, which prompted that mitochondrion plays a key role in DN, namely, mitochondrial fission is increasing under HG.…”

Section: Introductionmentioning

confidence: 99%

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

Zhang

Tang

et al. 2015

Renal Failure

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Diabetic nephropathy (DN) is a serious complication of diabetes with a poorly defined etiology and limited treatment options. Early intervention is a key to preventing the progression of DN. Dynamin-related protein 1 (DRP1) regulates mitochondrial morphology by promoting its fission and is involved in the pathogenesis of numerous diseases. Furthermore, DRP1 is also closely associated with the development of diabetes, but its functional role in DN remains unknown. This study investigated the effect of DRP1 on early stage of DN. DRP1 expression has increased significantly in glomerular mesangial cell (GMC), which is cultivated in high glucose (HG). Ultramicrostructural changes of nephrons, expression of collagen IV and phosph-p38, ROS production, and mitochondrial function were evaluated and, at the same time, were compared with glomerular mesangial cell (GMC) cultured in normal-glucose (NG), mannitol, and a medium with mitochondrial division inhibitor 1 (Midivi-1). Endogenous DRP1 expression increased in DN. Compared to the control groups ofNG and mannitol, overexpression of DRP1 destroyed pathological changes typical of the GMC, like accumulation of extracellular matrix, and an increase in mitochondria division. In addition, Overexpression of DRP1 promoted the activation of p38, the accumulation of ROS, mitochondrial dysfunction, and the synthesis of collagen IV, and all these changes are suppressed by Midivi-1. This study demonstrates that DRP1 overexpression can accelerate pathological changes in the GMC cultured in HG. Further studies are needed to clarify the underlying mechanism of this destructive function.

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NLRP3 Inflammasome Mediates Albumin-induced Renal Tubular Injury through Impaired Mitochondrial Function

Cited by 71 publications

References 38 publications

Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

Angiotensin II Stimulates the NLRP3 Inflammasome to Induce Podocyte Injury and Mitochondrial Dysfunction

Mitochondrial dysfunction confers albumin-induced NLRP3 inflammasome activation and renal tubular injury

Inhibition to DRP1 translocation can mitigate p38 MAPK-signaling pathway activation in GMC induced by hyperglycemia

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