Cyclin-dependent kinase 2 protects podocytes from apoptosis

Saurus, Pauliina; Kuusela, Sara; Dumont, Vincent; Lehtonen, Eero; Fogarty, Christopher L.; Lassenius, Mariann I.; Forsblom, Carol; Lehto, Markku; Saleem, Moin A.; Groop, Per‐Henrik

doi:10.1038/srep21664

Cited by 34 publications

(29 citation statements)

References 58 publications

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“…While TRAPP and COPII associate with SGs in undifferentiated podocytes in response to stress, this association was reduced in differentiated podocytes (Fig E). Of note, the proliferation to differentiation switch, as described (Saurus et al , ), is also accompanied by a decline in CDK activity (Fig F and G).…”

Section: Resultssupporting

confidence: 79%

The TRAPP complex mediates secretion arrest induced by stress granule assembly

et al. 2019

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The TRAnsport Protein Particle (TRAPP) complex controls multiple membrane trafficking steps and is strategically positioned to mediate cell adaptation to diverse environmental conditions, including acute stress. We have identified the TRAPP complex as a component of a branch of the integrated stress response that impinges on the early secretory pathway. The TRAPP complex associates with and drives the recruitment of the COPII coat to stress granules (SGs) leading to vesiculation of the Golgi complex and arrest of ER export. The relocation of the TRAPP complex and COPII to SGs only occurs in cycling cells and is CDK1/2‐dependent, being driven by the interaction of TRAPP with hnRNPK, a CDK substrate that associates with SGs when phosphorylated. In addition, CDK1/2 inhibition impairs TRAPP complex/COPII relocation to SGs while stabilizing them at ER exit sites. Importantly, the TRAPP complex controls the maturation of SGs. SGs that assemble in TRAPP‐depleted cells are smaller and are no longer able to recruit RACK1 and Raptor, two TRAPP‐interactive signaling proteins, sensitizing cells to stress‐induced apoptosis.

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Section: Resultssupporting

confidence: 79%

The TRAPP complex mediates secretion arrest induced by stress granule assembly

et al. 2019

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“…To define the reason for this, we investigated the expression of 3-phosphoinositide-dependent protein kinase 1 (PDK1) and cyclin-dependent kinase 2 (CDK2), both shown to induce apoptosis in podocytes when knocked down 17 , 18 . Interestingly, the expression of PDK1 was downregulated by 35% and CDK2 by 65% in CD2AP−/− podocytes when compared to wild type cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis

Saurus

Tolvanen

Lindfors

et al. 2017

Sci Rep

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Lack of CD2-associated protein (CD2AP) in mice increases podocyte apoptosis and leads to glomerulosclerosis and renal failure. We showed previously that SHIP2, a negative regulator of the PI3K/AKT signalling pathway, interacts with CD2AP. Here, we found that the expression level and activity of SHIP2 and production of reactive oxygen species (ROS) are increased in cultured CD2AP knockout (CD2AP−/−) mouse podocytes. Oxidative stress was also increased in CD2AP−/− mouse glomeruli in vivo. We found that puromycin aminonucleoside (PA), known to increase ROS production and apoptosis, increases SHIP2 activity and reduces CD2AP expression in cultured human podocytes. PDK1 and CDK2, central regulators of AKT, were downregulated in CD2AP−/− or PA-treated podocytes. Downregulation of PDK1 and CDK2, ROS generation and apoptosis were prevented by CD2AP overexpression in both models. Notably, inhibition of SHIP2 activity with a small molecule inhibitor AS1949490 ameliorated ROS production in CD2AP−/− podocytes, but, surprisingly, further reduced PDK1 expression and aggravated apoptosis. AKT- and ERK-mediated signalling was diminished and remained reduced after AS1949490 treatment in the absence of CD2AP. The data suggest that inhibition of the catalytic activity of SHIP2 is beneficial in reducing oxidative stress, but leads to deleterious increase in apoptosis in podocytes with reduced expression of CD2AP.

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“…It has been reported that PI3K/PTEN-PDK1 signalling in oocytes regulates the survival, loss, and activation of primordial follicles [24]. PDK1 is one of the activators of the Akt cell survival pathway and might be associated with the development of DKD through regulation of podocyte apoptosis [25,26]. The PDK1/Akt/mTOR pathway was activated both in diabetic rats and in human renal mesangial cells under high glucose condition [27].…”

Section: Discussionmentioning

confidence: 99%

Xuesaitong Protects Podocytes from Apoptosis in Diabetic Rats through Modulating PTEN-PDK1-Akt-mTOR Pathway

Xue

Zhai

Xie

et al. 2020

Journal of Diabetes Research

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Diabetic kidney disease (DKD) is a major cause of end-stage renal disease (ESRD), and therapeutic strategies for delaying its progression are limited. Loss of podocytes by apoptosis characterizes the early stages of DKD. To identify novel therapeutic options, we investigated the effects of Xuesaitong (XST), consisting of total saponins from Panax notoginseng, on podocyte apoptosis in streptozotocin- (STZ-) induced diabetic rats. XST (5 mg/kg·d) or Losartan (10 mg/kg·d) was given to diabetic rats for 12 weeks. Albuminuria, renal function markers, and renal histopathology morphological changes were examined. Podocyte apoptosis was determined by triple immunofluorescence labelling including a TUNEL assay, WT1, and DAPI. Renal expression of Nox4, miRNA-214, PTEN, PDK1, phosphorylated Akt, mTOR, and mTORC1 was detected. In diabetic rats, severe hyperglycaemia and albuminuria developed, and apoptotic podocytes were markedly increased in diabetic kidneys. However, XST attenuated albuminuria, mesangial expansion, podocyte apoptosis, and morphological changes of podocytes in diabetic rats. Decreased expression of PTEN, as well as increased expression of Nox4, miRNA-214, PDK1, phosphorylated Akt, mTOR, and mTORC1, was detected. These abnormalities were partially restored by XST treatment. Thus, XST ameliorated podocyte apoptosis partly through modulating the PTEN-PDK1-Akt-mTOR pathway. These novel findings might point the way to a natural therapeutic strategy for treating DKD.

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Cyclin-dependent kinase 2 protects podocytes from apoptosis

Cited by 34 publications

References 58 publications

The TRAPP complex mediates secretion arrest induced by stress granule assembly

The TRAPP complex mediates secretion arrest induced by stress granule assembly

Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis

Xuesaitong Protects Podocytes from Apoptosis in Diabetic Rats through Modulating PTEN-PDK1-Akt-mTOR Pathway

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