Angiotensin II induces cholesterol accumulation and injury in podocytes

Yang, Yingjie; Yang, Qian; Yang, Jian; Ma, Yiqiong; Ding, Guohua

doi:10.1038/s41598-017-09733-w

Cited by 48 publications

(58 citation statements)

References 30 publications

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“…A variety of risk factors promotes the development and progression of diabetic nephropathy, and among them, high glucose, high FFA, and angiotensin II are well-known risk factors, respectively. In previous studies, the administration of high glucose for 24 hours caused increase podocyte apoptosis [42], and stimulation with angiotensin II for 24 hours resulted in podocyte injury [43], and they were generally used for in vitro diabetic nephropathy models. In addition, previous studies have shown decreased insulin sensitivity and ceramide formation when treated with fatty acid [44][45][46].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

et al. 2020

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Background: Ceramides are associated with metabolic complications including diabetic nephropathy in patients with diabetes. Recent studies have reported that podocytes play a pivotal role in the progression of diabetic nephropathy. Also, mitochondrial dysfunction is known to be an early event in podocyte injury. Thus, we tested the hypothesis that ceramide accumulation in podocytes induces mitochondrial damage through reactive oxygen species (ROS) production in patients with diabetic nephropathy. Methods: We used Otsuka Long Evans Tokushima Fatty (OLETF) rats and high-fat diet (HFD)-fed mice. We fed the animals either a control-or a myriocin-containing diet to evaluate the effects of the ceramide. Also, we assessed the effects of ceramide on intracellular ROS generation and on podocyte autophagy in cultured podocytes. Results: OLETF rats and HFD-fed mice showed albuminuria, histologic features of diabetic nephropathy, and podocyte injury, whereas myriocin treatment effectively treated these abnormalities. Cultured podocytes exposed to agents predicted to be risk factors (high glucose, high free fatty acid, and angiotensin II in combination [GFA]) showed an increase in ceramide accumulation and ROS generation in podocyte mitochondria. Pretreatment with myriocin reversed GFA-induced mitochondrial ROS generation and prevented cell death. Myriocin-pretreated cells were protected from GFA-induced disruption of mitochondrial integrity. Conclusion: We showed that mitochondrial ceramide accumulation may result in podocyte damage through ROS production. Therefore, this signaling pathway could become a pharmacological target to abate the development of diabetic kidney disease.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

et al. 2020

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“…Additionally, patients with ABCA1 dysfunction and HDL deficiency tend to have chronic low-grade inflammation due to the anti-inflammatory effects of ABCA1 (Birjmohun et al, 2007 ; Westerterp et al, 2013 ; Bochem et al, 2015 ). The decreased ABCA1-mediated cholesterol efflux caused cholesterol-dependent apoptosis in podocytes (Yang et al, 2017b ). Therefore, cholesterol accumulation and the downregulation of the expression of ABCA1 in kidneys appear to promote diabetic kidney injury.…”

Section: Discussionmentioning

confidence: 99%

“…In a previous study, the cholesterol efflux was suppressed and the expression of ABCA1 was downregulated in high glucose-stimulated human glomerular endothelial cells (Yin et al, 2016 ). The downregulation of ABCA1 expression caused cholesterol-dependent apoptosis in podocytes (Yang et al, 2017b ). However, the level of ABCA1 expression in renal tubular cells and its role in renal tubular cell injury remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Tangshen Formula Attenuates Diabetic Nephropathy by Promoting ABCA1-Mediated Renal Cholesterol Efflux in db/db Mice

et al. 2018

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The commonly prescribed Tangshen Formula (TSF) is a traditional Chinese formulation that has been shown to reduce plasma lipid metabolism and proteinuria and improve the estimated glomerular filtration rate (eGFR) in patients with diabetic kidney disease. This study investigated the underlying mechanism whereby TSF regulates renal lipid accumulation and ameliorates diabetic renal injuries in spontaneous diabetic db/db mice and in vitro in sodium palmitate (PA)-stimulated and Abca1-SiRNA-transfected mouse tubular epithelial cells (mTECs). The results revealed that TSF treatment significantly ameliorated the renal injuries by lowering urinary albumin excretion and improving renal tissue injuries in diabetic (db/db) mice. Interestingly, the treatment with TSF also resulted in decreased cholesterol levels in the renal tissues of db/db mice, which was associated with increased expression of the peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), the Liver X receptors (LXR), and ATP-binding cassette subfamily A member 1 (ABCA1), suggesting that TSF might attenuate diabetic kidney injury via a mechanism associated with improving cholesterol efflux in the diabetic kidney. This was investigated in vitro in mTECs, and the results showed that TSF reduced the PA-stimulated cholesterol accumulation in mTECs. Mechanistically, the addition of TSF was capable of reversing PA-induced downregulation of PGC-1α, LXR, and ABCA1 expression and cholesterol accumulation in mTECs, suggesting that TSF might act the protection via the PGC-1α-LXR-ABCA1 pathway to improve the cholesterol efflux in the renal tissues of db/db mice. This was further confirmed by silencing ABCA1 to block the promotive effect of TSF on cholesterol efflux in vitro. In conclusion, TSF might ameliorate diabetic kidney injuries by promoting ABCA1-mediated renal cholesterol efflux.

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“…However, Ang II also contributes to the pathogenesis of various diseases, mainly by inducing oxidative stress, inflammation, cholesterol accumulation, and fibrosis [3-5]. Moreover, accumulating evidence shows that inflammation plays an important role in the development and progression of renal diseases [6-8].…”

Section: Introductionmentioning

confidence: 99%

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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Angiotensin II induces cholesterol accumulation and injury in podocytes

Cited by 48 publications

References 30 publications

Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

Inhibition of Ceramide Accumulation in Podocytes by Myriocin Prevents Diabetic Nephropathy

Tangshen Formula Attenuates Diabetic Nephropathy by Promoting ABCA1-Mediated Renal Cholesterol Efflux in db/db Mice

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

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