Angiotensin II Type I Receptor Agonistic Autoantibody Induces Podocyte Injury via Activation of the TRPC6- Calcium/Calcineurin Pathway in Pre-Eclampsia

Yu, Ying; Zhang, Lihong; Xu, Guang; Wu, Zhenghong; Li, Qian; Gu, Yong; Niu, Jianying

doi:10.1159/000494744

Cited by 19 publications

(16 citation statements)

References 37 publications

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“…Some researchers have reported the potential mechanism by which Ang II decreases the nephrin and podocin expression. In order to explore the mechanism of podocyte injury induced by Ang II, Yu et al (67) treated human podocytes with various concentrations of Ang II type I receptor agonistic autoantibody (AT1-AA); the results revealed that AT1-AA decreased the expression of nephrin in a dose-dependent manner and the underlying mechanism might involve activation of the transient receptor potential cation channer subfamily C member 6-calcium/calcineurin pathway (67). A similar conclusion was drawn in another study of Zhao et al (68).…”

Section: Discussionmentioning

confidence: 99%

Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury

Wang

Senouthai

et al. 2019

Mol Med Report

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Numerous studies have reported that angiotensin (Ang) II, nephrin, and podocin serve pivotal roles in podocyte injury, and thus can lead to the occurrence of proteinuria and the progression of kidney diseases. This study aimed to investigate the effects of Ang II on the production of nephrin and podocin, and their relationship with podocyte injury. We also aimed to determine whether nephrin, podocin and caspase-9 production depends on the PI3K/Akt/nuclear factor (NF)-κB signaling pathway in cultured mouse podocytes. We treated mouse podocytes with different doses of Ang II (10−9, 10−8, 10−7 and 10−6 mol/l) for 12, 24, and 48 h to analyse cell viability, and at 10−6 mol/l Ang II for 12, 24, and 48 h to evaluate cell apoptosis. Cells were treated with 10−6 mol/l of Ang II and/or LY294002 (inhibitor of Akt) or 740Y-P (activator of PI3K) for 48 h to detect Akt, phosphorylated (phospho)-Akt, p65 NF-κB, and phospho-p65 NF-κB, nephrin, podocin and caspase-9 expression, and podocyte apoptosis. Treatment with Ang II suppressed the viability and promoted the apoptosis of podocytes in a dose- and time-dependent manner. Ang II decreased phospho-Akt, phospho-p65 NF-κB, nephrin, and podocin and increased caspase-9 expression, while podocyte apoptosis was promoted. LY294002 further enhanced Ang II-induced downregulation of Akt and p65 NF-κB activation, as well as upregulation of caspase-9 mRNA and protein, and promoted the apoptosis of podocytes. Of note, 740Y-P restored Ang II-induced downregulation of Akt and p65 NF-κB activation, and upregulation of caspase-9, and decreased podocyte apoptosis. Interestingly, LY294002 and 740Y-P were determined to have no notable effects on the expression of nephrin and podocin. The data suggested that Ang II could regulate the expression of nephrin, podocin and caspase-9. Collectively, our findings suggested that the PI3K/Akt/NF-κB survival axis may serve a pivotal role in podocyte injury.

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Section: Discussionmentioning

confidence: 99%

Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury

Wang

Senouthai

et al. 2019

Mol Med Report

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“…Furthermore, gain‐of‐function mutations of TRPC6 protein increase ERK1/2 phosphorylation (Chiluiza et al, 2013). The upregulation of ERK1/2 leads to higher TRPC6 expression, which in turn induces podocyte injury (Yu et al, 2018). Pit 1/Pit 2 heterodimers can mediate ERK signaling, and ERK1/2 affects TRPC6 channel activity.…”

Section: The Function Of Slc20 Proteins In the Podocyte: Future Perspectivementioning

confidence: 99%

The impact of type III sodium‐dependent phosphate transporters (Pit 1 and Pit 2) on podocyte and kidney function

Kulesza

Piwkowska

2021

Journal Cellular Physiology

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The sodium‐dependent phosphate transporters Pit 1 and Pit 2 belong to the solute carrier 20 (SLC20) family of membrane proteins. They are ubiquitously distributed in the human body. Their crucial function is the intracellular transport of inorganic phosphate (Pi) in the form of H2PO4 −. They are one of the main elements in maintaining physiological phosphate homeostasis. Recent data have emerged that indicate novel roles of Pit 1 and Pit 2 proteins besides the well‐known function of Pi transporters. These membrane proteins are believed to be precise phosphate sensors that mediate Pi‐dependent intracellular signaling. They are also involved in insulin signaling and influence cellular insulin sensitivity. In diseases that are associated with hyperphosphatemia, such as diabetes and chronic kidney disease (CKD), disturbances in the function of Pit 1 and Pit 2 are observed. Phosphate transporters from the SLC20 family participate in the calcification of soft tissues, mainly blood vessels, during the course of CKD. The glomerulus and podocytes therein can also be a target of pathological calcification that damages these structures. A few studies have demonstrated the development of Pi‐dependent podocyte injury that is mediated by Pit 1 and Pit 2. This paper discusses the role of Pit 1 and Pit 2 proteins in podocyte function, mainly in the context of the development of pathological calcification that disrupts permeability of the renal filtration barrier. We also describe the mechanisms that may contribute to podocyte damage by Pit 1 and Pit 2.

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“…Recent studies revealed progressive aggravation of proteinuria, decreased renal function, and ultimately glomerular fibrosis associated with increased expression of TRPC6 in the model of ischemia-reperfusion acute kidney injury [91]. Contribution of TRPC6-mediated calcium pathways and podocyte injury in pre-eclampsia was also proposed [92].…”

Section: Role Of Trpc6 In Other Ckdmentioning

confidence: 99%

Role of TRPC6 in Progression of Diabetic Kidney Disease

2019

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Purpose of Review: The underlining goal of this review is to offer a concise, detailed look into current knowledge surrounding transient receptor potential canonical channel 6 (TRPC6) in the progression of diabetic kidney disease (DKD). Recent Findings: Mutations and over-activation in TRPC6 channel activity lead to the development of glomeruli injury. Angiotensin II, reactive oxygen species and other factors in the setting of DKD stimulate drastic increases in calcium influx through the TRPC6 channel, causing podocyte hypertrophy and foot process effacement. Loss of the podocytes further deteriorates the glomerular filtration barrier and the characteristic in renal injury of DKD follows. Recent genetic manipulation with TRPC6 channels in various rodent models provide additional knowledge about the role of TRPC6 in DKD and are reviewed here. Summary: The TRPC6 channel has a pronounced role in the progression of DKD, with deviations in activity yielding detrimental outcomes. The benefits of targeting TRPC6 or its upstream or downstream signaling pathways in DKD are prominent.

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Angiotensin II Type I Receptor Agonistic Autoantibody Induces Podocyte Injury via Activation of the TRPC6- Calcium/Calcineurin Pathway in Pre-Eclampsia

Cited by 19 publications

References 37 publications

Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury

Critical roles of PI3K/Akt/NF‑κB survival axis in angiotensin II‑induced podocyte injury

The impact of type III sodium‐dependent phosphate transporters (Pit 1 and Pit 2) on podocyte and kidney function

Role of TRPC6 in Progression of Diabetic Kidney Disease

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