Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function

Hurcombe, Jenny A; Lay, Abigail C; Ni, Lan; Barrington, A Fern; Woodgett, Jim; Quaggin, Susan E.; Welsh, Gavin I.; Coward, Richard J M

doi:10.1096/fba.2019-00011

Cited by 8 publications

(6 citation statements)

References 48 publications

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“…In our data, PCOS mice had a significantly increased production of the pro-inflammatory cytokine, which was consistent with the previous study, and sh-UCA1 markedly inhibited the production of pro-inflammatory cytokine. Combined with previous reports, a high level of insulin promoted the initiation of inflammation, and insulin resistance was aggravated by the inflammatory environment [34,37]. Our data indicated that lncRNA UCA1 participated in the pathophysiology of PCOS, through an insulin-inflammation cycle.…”

Section: Discussionsupporting

confidence: 85%

Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway

et al. 2021

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Background Polycystic ovary syndrome (PCOS) is the most common hormonal disorder among reproductive-aged women worldwide, however, the mechanisms and progression of PCOS still unclear due to its heterogeneous nature. Using the human granulosa-like tumor cell line (KGN) and PCOS mice model, we explored the function of lncRNA UCA1 in the pathological progression of PCOS. Results CCK8 assay and Flow cytometry were used to do the cell cycle, apoptosis and proliferation analysis, the results showed that UCA1 knockdown in KGN cells inhibited cell proliferation by blocking cell cycle progression and promoted cell apoptosis. In the in vivo experiment, the ovary of PCOS mice was injected with lentivirus carrying sh-UCA1, the results showed that knockdown of lncRNA UCA1 attenuated the ovary structural damage, increased the number of granular cells, inhibited serum insulin and testosterone release, and reduced the pro-inflammatory cytokine production. Western blot also revealed that UCA1 knockdown in PCOS mice repressed AKT activation, inhibitor experiment demonstrated that suppression of AKT signaling pathway, inhibited the cell proliferation and promoted apoptosis. Conclusions Our study revealed that, in vitro, UCA1 knockdown influenced the apoptosis and proliferation of KGN cells, in vivo, silencing of UCA1 regulated the ovary structural damage, serum insulin release, pro-inflammatory production, and AKT signaling pathway activation, suggesting lncRNA UCA1 plays an important role in the pathological progression of PCOS.

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Section: Discussionsupporting

confidence: 85%

Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway

et al. 2021

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“…The loss of the GSK3α/mTORC1 axis promotes exacerbated spermatogonial differentiation, leading to the depletion of germ cells [ 25 ]. Similar results have been reported in podocytes, in which GSK3α KO promotes cell death and impairs autophagy, which results in a detrimental glomerular function; in this case, however, no link to mTORC1 has been reported [ 26 ]. These effects could involve the differential regulation of gene expression because, while it is well-established that GSK3β and GSK3α have preference over some transcriptional factors, it has been reported that GSK3α is the main isoform that represses the activity of CREB, NF-κB, and mothers of decantaplegic homolog protein 3 and 4 (SMAD3/4) in neuronal cell cultures [ 27 ].…”

Section: The Relevance Of Gsk3αsupporting

confidence: 85%

GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer

et al. 2020

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The biological activity of the enzyme glycogen synthase kinase-3 (GSK3) is fulfilled by two paralogs named GSK3α and GSK3β, which possess both redundancy and specific functions. The upregulated activity of these proteins is linked to the development of disorders such as neurodegenerative disorders (ND) and cancer. Although various chemical inhibitors of these enzymes restore the brain functions in models of ND such as Alzheimer’s disease (AD), and reduce the proliferation and survival of cancer cells, the particular contribution of each paralog to these effects remains unclear as these molecules downregulate the activity of both paralogs with a similar efficacy. Moreover, given that GSK3 paralogs phosphorylate more than 100 substrates, the simultaneous inhibition of both enzymes has detrimental effects during long-term inhibition. Although the GSK3β kinase function has usually been taken as the global GSK3 activity, in the last few years, a growing interest in the study of GSK3α has emerged because several studies have recognized it as the main GSK3 paralog involved in a variety of diseases. This review summarizes the current biological evidence on the role of GSK3α in AD and various types of cancer. We also provide a discussion on some strategies that may lead to the design of the paralog-specific inhibition of GSK3α.

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“…Insulin signalling to the podocyte via the IR is critical for podocyte function (14)(15)(16)(17) and it is apparent that IGF signalling is also important for podocyte homeostasis (18)(19)(20). Recently we have shown that loss of podocyte IGF1 signalling can have both detrimental and beneficial effects dependent upon the level of IGF1R suppression: whilst near total loss of podocyte IGF1R expression results in severe mitochondrial dysfunction associated with cell death, partial receptor inhibition promotes podocyte survival in conditions of cellular stress (21).…”

Section: Introductionmentioning

confidence: 99%

The insulin / IGF axis is critically important controlling gene transcription in the podocyte

Hurcombe,

Dayalan,

Barrington

et al. 2024

Preprint

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Signalling to the podocyte via the structurally related insulin receptor (IR) or insulin-like growth factor 1 receptor (IGF1) is important for podocyte function. This study sought to elucidate the compound role of the insulin/IGF1 axis in podocytes using transgenic mice and cell culture models deficient in both receptors. Podocyte specific IR/IGF1R knockdown mice developed a severe kidney phenotype with albuminuria, glomerulosclerosis and renal failure with death occurring in some mice between 4 and 24 weeks. Simultaneous knockdown of both receptors in cultured podocytes resulted in >50% cell death by 7 days. Proteomic analysis revealed a striking downregulation of spliceosome-related proteins in IR/IGF1R knockdown podocytes with long-read RNA sequence data indicating an increased fraction of transcripts with intron retention/premature termination codons in these cells. This work underlines the critical importance of podocyte insulin/IGF signalling revealing a novel role for this extrinsic hormonal signalling axis in regulating gene transcription.

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Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function

Cited by 8 publications

References 48 publications

Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway

Silencing of lncRNA UCA1 inhibited the pathological progression in PCOS mice through the regulation of PI3K/AKT signaling pathway

GSK3α: An Important Paralog in Neurodegenerative Disorders and Cancer

The insulin / IGF axis is critically important controlling gene transcription in the podocyte

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