Angiotensin II induces endoplasmic reticulum stress in podocyte, which would be further augmented by PI3-kinase inhibition

Ha, Tae-Sun; Park, Hye-Young; Seong, Su-Bin; Ahn, Hee Yul

doi:10.1186/s40885-015-0018-5

Cited by 17 publications

(17 citation statements)

References 36 publications

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“…ACE2 counterbalances the effects of the classic RAS through conversion of Ang II to Ang‐(1‐7). Ang II has been reported to induce podocyte ERS via GRP78/eIF2α/ATF4/CHOP axis . In the present study, the changes in GRP78/ATF4/CHOP expression in ACE2 KO mice and Ad‐ACE2–treated db/db mice suggested that Ang II and ACE2 induce ERS may through the same pathway.…”

Section: Discussionsupporting

confidence: 58%

Angiotensin‐converting enzyme 2 inhibits endoplasmic reticulum stress–associated pathway to preserve nonalcoholic fatty liver disease

Cao

Song

Zhang

et al. 2019

Diabetes Metabolism Res

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Background: Previous works indicated that the stress on the endoplasmic reticulum (ER) affected nonalcoholic fatty liver disease (NAFLD). However, there is no clear evident on the effect of the regulation of ER stress by angiotensin-converting enzyme 2 (ACE2) on the prevention of NAFLD.Methods: HepG2 cells were treated with thapsigargin (Tg) or palmitic acid (PA).We analysed ACE2 expression using Western-blotting analyses. ER stress-related proteins were detected in ACE2 knockout mice and Ad-ACE2-treated db/db mice by immunofluorescence or Western-blotting analyses. In ACE2-overexpression HepG2 cells, the triglyceride (TG), total cholesterol (TC), and glycogen content were detected by assay kits. Meanwhile, the expression of hepatic lipogenic proteins (ACCα, SREBP-1c, FAS, and LXRα), enzymes for gluconeogenesis (PEPCK, G6Pase, and IRS2), and IKKβ/NFκB/IRS1/Akt pathway were analysed by Western-blotting analyses.Results: ACE2 was significantly increased in Tg/PA-induced cultured hepatocytes.Additionally, ACE2 knockout mice displayed elevated levels of ER stress, while Ad-ACE2-treated db/db mice showed reduced ER stress in liver. Furthermore, activation of ACE2 can ameliorate ER stress, accompanied by decreased TG content, increased intracellular glycogen, and downregulated expression of hepatic lipogenic proteins and enzymes for gluconeogenesis in Tg/PA-induced hepatocytes. As a consequence of anti-ER stress, the activation of ACE2 led to improved glucose and lipid metabolism through the IKKβ/NFκB/IRS1/Akt pathway.Conclusions: This is the first time documented that ACE2 had a notable alleviating role in ER stress-induced hepatic steatosis and glucose metabolism via the IKKβ/NFκB/IRS1/Akt-mediated pathway. This study may further provide insight into a novel underlying mechanism and a strategy for treating NAFLD. KEYWORDS ACE2, endoplasmic reticulum, glucose metabolism, hepatic steatosis Xi Cao and Li-Ni Song contribute equally to this article.

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Section: Discussionsupporting

confidence: 58%

Angiotensin‐converting enzyme 2 inhibits endoplasmic reticulum stress–associated pathway to preserve nonalcoholic fatty liver disease

Cao

Song

Zhang

et al. 2019

Diabetes Metabolism Res

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“…ER stress is common under various pathogenic microenvironments and contributes to progression of various podocyte diseases. Abnormal protein accumulation associated with podocyte-specific ER stress induces structural and functional damage in cells, which in turn leads to apoptosis and severe proteinuria [ 21 – 23 ]. The ER stress mechanisms underlying the development of podocyte injury by PAN remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplasmic reticulum stress

Min

2018

Kidney Res Clin Pract.

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BackgroundPuromycin aminonucleoside (PAN) is a known podocytotoxin. PAN-induced nephrosis is a widely used animal model for studying human idiopathic nephrotic syndrome. Abnormal protein accumulation associated with podocyte-specific endoplasmic reticulum (ER) stress damages cells structurally and functionally, which in turn induces apoptosis and severe proteinuria. In the present study, we investigated the effect of PAN on ER stress and apoptosis in podocytes in vitro.MethodsMouse podocytes were cultured and treated with various concentrations of PAN. ER stress markers were then evaluated by western blotting, and apoptosis was evaluated by fluorescence-activated cell sorting (FACS) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays.ResultsPAN treatment increased ER stress markers such as activating transcription factor (ATF) 6α and caspase-12 in a dose-dependent manner at 12 and 24 hours, respectively. These markers were reduced by chemical chaperones, such as sodium 4-phenylbutyric acid and tauroursodeoxycholic acid. PAN treatment also increased 78 kD glucose-regulated protein (GRP78)/binding immunoglobulin protein (BiP) at the earlier stage of 12 hours. PAN significantly induced podocyte apoptosis in concentration- and time-dependent manners, as seen using FACS and TUNEL assays. This result was improved by Nox4 siRNA, ATF6 siRNA, and chemical chaperones. LY294002, a PI3-kinase inhibitor, significantly boosted ER stress and apoptosis. PAN-induced ER stress increased oxidative stress and subsequently induced apoptosis, and could be mitigated by inhibition of PI3-kinase signaling.ConclusionOur findings suggest that PAN induces ER stress in podocytes mainly through the GRP78/BiP, ATF6α, and caspase-12 pathways, which trigger apoptosis via induction of oxidative stress. This stress is mitigated by inhibiting PI3-kinase signaling.

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“…However, this Ang II/ER stress/SREBP activation needs to be confirmed in experimental animal models to provide stronger evidence. As Ang II might also induce ER stress in podocytes (Ha et al, 2015) and proximal tubular epithelial cells (Wang J. et al, 2015), other studies with these kidney cell subtypes are needed, as well. EGFR may be an important second signal in TGFβ upregulation via activation of the SREBP1 cotranscription factor Sp1.…”

Section: Srebp Induces Tgfβ Transcriptional Activitymentioning

confidence: 99%

Recent Insights Into SREBP as a Direct Mediator of Kidney Fibrosis via Lipid-Independent Pathways

Dorotea

Koya

2020

Front. Pharmacol.

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Sterol regulatory-element binding proteins (SREBPs) are classical regulators of cellular lipid metabolism in the kidney and other tissues. SREBPs are currently recognized as versatile transcription factors involved in a myriad of cellular processes. Meanwhile, SREBPs have been recognized to mediate lipotoxicity, contributing to the progression of kidney diseases. SREBP1 has been shown to bind to the promoter region of TGFβ, a major pro-fibrotic signaling mechanism in the kidney. Conversely, TGFβ activates SREBP1 transcriptional activity suggesting a positive feedback loop of SREBP1 in TGFβ signaling. Public ChIP-seq data revealed numerous non-lipid transcriptional targets of SREBPs that plausibly play roles in progressive kidney disease and fibrosis. This review provides new insights into SREBP as a mediator of kidney fibrosis via lipid-independent pathways.

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Angiotensin II induces endoplasmic reticulum stress in podocyte, which would be further augmented by PI3-kinase inhibition

Cited by 17 publications

References 36 publications

Angiotensin‐converting enzyme 2 inhibits endoplasmic reticulum stress–associated pathway to preserve nonalcoholic fatty liver disease

Angiotensin‐converting enzyme 2 inhibits endoplasmic reticulum stress–associated pathway to preserve nonalcoholic fatty liver disease

Puromycin aminonucleoside triggers apoptosis in podocytes by inducing endoplasmic reticulum stress

Recent Insights Into SREBP as a Direct Mediator of Kidney Fibrosis via Lipid-Independent Pathways

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