Angiotensin II promotes podocyte injury by activating Arf6-Erk1/2-Nox4 signaling pathway

Che, Guanghua; Gao, Hang; Hu, Qibo; Xie, Hongsheng; Zhang, Yunfeng

doi:10.1371/journal.pone.0229747

Cited by 21 publications

(20 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, reduction in Erk pathway signaling has been reported to inhibit beta cell apoptosis [52], and specific blockade of the Erk pathway improves insulin resistance in diabetic mice [53]. Previous reports including our results suggested that the activation of Erk is a critical step in the regulation of STZ-or angiotensin II-induced Nox4 expression [54,55]. Some potential antioxidant agents, such as hispidin and sodium hydrogen sulfide, markedly reduced p-Erk, and treatment with an Erk inhibitor (U0126) reduced high glucose-induced cardiomyocyte injury by decreasing ROS generation [56].…”

Section: Discussionsupporting

confidence: 67%

Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

Kim

Yoon

et al. 2020

Antioxidants

View full text Add to dashboard Cite

Pancreatic beta cells are vulnerable to oxidative stress, which causes beta cell death and dysfunction in diabetes mellitus. Broussonetia kazinoki Siebold (BK) is a widely used herbal medicine, but its potential effects against beta cell death-induced diabetes have not been studied. Therefore, we investigated the protective effect of an ethanolic extract of BK fruit (BKFE) against streptozotocin (STZ)-induced toxicity in pancreatic beta cells. Intraperitoneal injection of STZ in mice induced hyperglycemia; however, oral administration of BKFE significantly decreased the blood glucose level as well as HbA1c levels. BKFE treatment improved glucose tolerance and increased body weight in diabetic mice. Moreover, BKFE treatment resulted in increased serum insulin levels and insulin expression in the pancreas as well as decreased 4-hydroxynonenal levels induced by oxidative stress. Treatment with STZ decreased cell viability of mouse insulinoma cells (MIN6), which was blocked by BKFE pretreatment. BKFE significantly inhibited apoptotic cells and decreased the expression levels of cleaved-caspase-3 and cleaved-poly (ADP-ribose) polymerase (PARP) induced by STZ treatment. Production of reactive oxygen species in STZ-treated MIN6 cells was also significantly decreased by treatment with BKFE. Erk phosphorylation and Nox4 levels increased in STZ-treated MIN6 cells and the pancreas of mice injected with STZ and this increase was inhibited by treatment with BKFE. Inhibition of Erk phosphorylation by treatment with the PD98059 inhibitor or siRNA Erk also blocked the expression of Nox4 induced by STZ treatment. In conclusion, BKFE inhibits Erk phosphorylation, which in turn prevents STZ-induced oxidative stress and beta cell apoptosis. These results suggested that BKFE can be used to prevent or treat beta cell damage in diabetes.

show abstract

Section: Discussionsupporting

confidence: 67%

Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

Kim

Yoon

et al. 2020

Antioxidants

View full text Add to dashboard Cite

show abstract

“…However, in contrast with ISP exposure in vivo , daidzein alone did not induce changes in expression or activation of ERK1/2 or Akt in male podocytes in vitro , and no changes in activated or total Akt were seen in high glucose-treated cells ( Figure 6A-6C ). In female-derived cells, which required inclusion of angiotensin in the injury model to increase ERK1/2 activation, 51 treatment with daidzein similarly suppressed the effects of high glucose ( Figure 6A and 6C ). A comparable overall effect was seen with p38 activation, which is another mitogen-activated protein kinase (MAPK) pathway associated with podocyte injury ( Supplemental Figure 4 ).…”

Section: Resultsmentioning

confidence: 90%

Sex Differences in Glomerular Protein Expression and Effects of Soy-Based Diet on Podocyte Signaling

Mahesaniya

Williamson

Chahi

et al. 2022

Can J Kidney Health Dis

View full text Add to dashboard Cite

Background: Kidney disease is a major public health issue arising from loss of glomerular podocyte function, and there are considerable sex differences in its prognosis. Evidence suggests a renoprotective effect of estrogen and soy diet-derived phytoestrogens, although the molecular basis for this is poorly understood. Objective: Here, we aim to assess sex differences in expression of key proteins associated with podocyte survival and determine the effects of dietary soy on glomerular and podocyte signaling. Methods: Male and female FVB mice were fed control, low (1%), and high (20%) doses of isolated soy protein (ISP) in utero and until 100 days of age. Spot urine was collected to measure proteinuria and isolated glomeruli were used to quantify activated and total levels of nephrin, Akt, and ERK1/2. To investigate protective effects of specific soy phytoestrogens, cultured podocytes were treated with or without daidzein and subject to control or high glucose as a model of podocyte injury. Results: Nephrin and Akt were elevated at baseline in glomeruli from females compared to males. Both sexes that were fed 1% and 20% ISP displayed robust increases in total glomerular Akt compared to controls, and these effects were more prominent in females. A similar trend at both doses in both sexes was observed with activated Akt and total nephrin. Notably, males exclusively showed increased phosphorylation of nephrin and extracellular signal-regulated kinase (ERK) at the 1% ISP dose; however, no overt changes in urinary albumin excretion or podocin levels were observed, suggesting that the soy diets did not impair podocyte function. Finally, in cultured male and female podocytes, daidzein treatment suppressed high glucose-induced ERK activation. Conclusions: Together, our findings reveal a putative mechanism to explain the protective influence of sex on kidney disease progression, and they provide further evidence to support a beneficial role for dietary soy in preserving glomerular function.

show abstract

“…As such, if and how Nox4 expression is regulated by PKA signaling in HG-induced podocyte injury needs be further investigated. Our recent findings demonstrated that Nox4-dependent ROS production is responsible for apoptosis through a small GTPase Arf6-mediated Erk1/2 activation in angiotensin II (Ang II)-treated podocytes ( Che et al, 2020 ). The mammalian target of the rapamycin (mTOR) signaling cascade controls cellular metabolism, survival and growth.…”

Section: Discussionmentioning

confidence: 99%

“…As described previously ( Che et al, 2020 ), apoptotic cell death was assessed with the Fluorescein In-Situ Cell Death Detection Kit (Sigma-Aldrich) according to the manufacturer's procedure. Nuclei were stained with the 4′,6-diamidino-2-phenylindole (DAPI).…”

Section: Methodsmentioning

confidence: 99%

High glucose induces Nox4 expression and podocyte apoptosis through the Smad3/ezrin/PKA pathway

et al. 2021

Self Cite

View full text Add to dashboard Cite

Podocyte is the major target in proteinuric kidney disease such as diabetic nephropathy. The underlying molecular mechanisms by which high glucose (HG) results in podocyte damage remain unclear. This study investigated the regulatory role of Smad3, ezrin, and protein kinase A (PKA) in NADPH oxidase (Nox4) expression, reactive oxidative species (ROS) production, and apoptosis in HG-treated podocytes. Human podocyte cell line was cultured and differentiated, then treated with 30 mM HG. Apoptosis and intracellular ROS level was assessed using TUNEL and DCF assay, respectively. Expressions of Nox4, phospho-Smad3Ser423/425, phospho-PKAThr197, and phospho-ezrinThr567 were evaluated using Western blotting. ELISA was used to quantify intracellular cAMP concentration and PKA activity. Knockdown assay was used to inhibit the expressions of Smad3, Nox4, and ezrin by lentiviral shRNA. In HG-treated podocytes, the level of phospho-Smad3Ser423/425 and phospho-ezrinThr567 was increased significantly, which was accompanied by the reduction of cAMP and phospho-PKAThr197. HG-induced apoptosis was significantly prevented by the Smad3 inhibitor SIS3 or shRNA-Smad3. In podocytes expressing shRNA-ezrin or shRNA-Nox4, apoptosis was remarkably mitigated following HG treatment. HG-induced upregulation of phospho-ezrinThr567 and downregulation of phospho-PKAThr197 was significantly prevented by SIS3, shRNA-ezrin or shRNA-Smad3. Forskolin, a PKA activator, significantly inhibited HG-mediated upregulation of Nox4 expression, ROS generation, and apoptosis. Additionally, an increase in the ROS level was prohibited in HG-treated podocytes with the knockdown of Nox4, Smad3, or ezrin. Taken together, our findings provided evidence that Smad3-mediated ezrin activation upregulates Nox4 expression and ROS production, by suppressing PKA activity, which may at least in part contribute to HG-induced podocyte apoptosis.

show abstract

Angiotensin II promotes podocyte injury by activating Arf6-Erk1/2-Nox4 signaling pathway

Cited by 21 publications

References 40 publications

Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

Prevention of Oxidative Stress-Induced Pancreatic Beta Cell Damage by Broussonetia kazinoki Siebold Fruit Extract via the ERK-Nox4 Pathway

Sex Differences in Glomerular Protein Expression and Effects of Soy-Based Diet on Podocyte Signaling

High glucose induces Nox4 expression and podocyte apoptosis through the Smad3/ezrin/PKA pathway

Contact Info

Product

Resources

About