Glycogen synthase kinase-3β promotes cyst expansion in polycystic kidney disease

Tao, Shixin; Kakade, Vijayakumar R.; Woodgett, James R.; Pandey, Pankaj; Suderman, Erin D.; Rajagopal, Madhumitha; Rao, Reena

doi:10.1038/ki.2014.427

Cited by 44 publications

(47 citation statements)

References 72 publications

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“…The two isoforms of GSK3, GSK3α and GSK3β, have been recently shown to have distinct distributions in distal nephrons . In mouse kidney, both the α and the β isoforms were evidently expressed in mouse renal parenchyma, as shown by immunoperoxidase staining (Figure A).…”

Section: Resultsmentioning

confidence: 86%

“…This effect was dramatically attenuated in KO podocytes, suggesting a direct protective effect of GSK3β knockout on mitochondria injury. Dual colour staining for cleaved caspase-3 and mitochondria demonstrated that mitochondrial damage preceded overt apoptosis, and both were sequentially mitigated in KO podocytes upon ADR insult, inferring that the GSK3β mediates podocyte autonomous injury 33 lessened mitochondrial damage in KO podocytes is a primary effect of GSK3β ablation rather than an effect secondary to the anti-apoptotic action. Our latest data indicated that Cyp-F, a core structural constituent of the mitochondria permeability transition (MPT) pores, is a substrate for GSK3β [4].…”

Section: Gsk3β Knockout Mitigates the Adr-elicited Mitochondria Dysfumentioning

confidence: 95%

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The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Dworkin

et al. 2016

J. Pathol.

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Converging evidence points to glycogen synthase kinase (GSK) 3 as a key player in the pathogenesis of podocytopathy and proteinuria. However, it remains unclear if GSK3 is involved in podocyte autonomous injury in glomerular disease. In normal kidneys, the β isoform of GSK3 was found to be the major GSK3 expressed in glomeruli and intensely stained in podocytes. GSK3β expression in podocytes was markedly elevated in experimental or human proteinuric glomerulopathy. Podocyte specific somatic ablation of GSK3β in adult mice attenuated proteinuria and ameliorated podocyte injury and glomerular damage in experimental adriamycin (ADR) nephropathy. Mechanistically, actin cytoskeleton integrity in podocytes was largely preserved in GSK3β knockout mice following ADR insult, concomitant with a correction of podocyte hypermotility and lessened phosphorylation and activation of paxillin, a focal adhesion associated adaptor protein. In addition, GSK3β knockout diminished ADR induced NFκB RelA/p65 phosphorylation selectively at serine 467, suppressed de novo expression by podocytes of NFκB dependent podocytopathic mediators, including B7-1, cathepsin L and MCP-1, but barely affected the induction of NFκB target prosurvival factors, such as Bcl-xL. Moreover, the ADR-elicited podocytopenia and podocyte death was significantly attenuated in GSK3β knockout mice, associated with a protection against podocyte mitochondrial damage and reduced phosphorylation and activation of cyclophilin F, a structural component of mitochondria permeability transition pores. Overall, our findings suggest that the β isoform of GSK3 mediates autonomous podocyte injury in glomerulopathy by integrating multiple podocytopathic signalling pathways.

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Section: Resultsmentioning

confidence: 86%

Section: Gsk3β Knockout Mitigates the Adr-elicited Mitochondria Dysfumentioning

confidence: 95%

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Dworkin

et al. 2016

J. Pathol.

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“…Ilk +/+ PKD kidneys showed a significant increase in ERK activity compared with WT. 55 Loss of one allele of ILK decreased P-ERK; however, this was NS. By contrast, ILK ablation in Ilk 2/2 PKD kidneys significantly reduced P-ERK.…”

Section: Effect Of Ilk On Cystic Diseasementioning

confidence: 90%

Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Raman

Reif²,

Dai³

et al. 2017

JASN

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Autosomal dominant polycystic kidney disease (ADPKD) is characterized by innumerous fluid-filled cysts and progressive deterioration of renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is markedly overexpressed by cyst epithelial cells. Periostin promotes cell proliferation, cyst growth, interstitial fibrosis, and the decline in renal function in PKD mice. Here, we investigated the regulation of these processes by the integrin-linked kinase (ILK), a scaffold protein that links the extracellular matrix to the actin cytoskeleton and is stimulated by periostin. Pharmacologic inhibition or shRNA knockdown of ILK prevented periostin-induced Akt/mammalian target of rapamycin (mTOR) signaling and ADPKD cell proliferation Homozygous deletion of ILK in renal collecting ducts (CD) of ; mice caused tubule dilations, apoptosis, fibrosis, and organ failure by 10 weeks of age. By contrast, ; mice had normal renal morphology and function and survived >1 year. Reduced expression of ILK in ; mice, a rapidly progressive model of ADPKD, decreased renal Akt/mTOR activity, cell proliferation, cyst growth, and interstitial fibrosis, and significantly improved renal function and animal survival. Additionally, CD-specific knockdown of ILK strikingly reduced renal cystic disease and fibrosis and extended the life of mice, a slowly progressive PKD model. We conclude that ILK is critical for maintaining the CD epithelium and renal function and is a key intermediate for periostin activation of signaling pathways involved in cyst growth and fibrosis in PKD.

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“…63 Fourth, pharmacological inhibition of glucogen synthase kinase 3 beta (GSK3beta), which accelerates cyst formation in cpk mice, leads to decreased Myc expression and amelioration of the cystic phenotype. 64 Similarly, Myc is down-regulated in Cys1 cpk/cpk ;Smad3 +/mice and such double mutants have a milder phenotype than cpk mice. 25 Our findings that complementation of mutant cpk with cystin-GFP rescues the cystic phenotype and restores normal Myc expression confirms that cystin acts in vivo as a negative regulator of Myc.…”

Section: Discussionmentioning

confidence: 99%

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

Yang¹,

O’Connor²,

Kesterson

et al. 2020

Preprint

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Mutation of the Cys1 gene underlies the renal cystic disease in the Cys1 cpk/cpk (cpk) mouse that phenocopies human autosomal recessive polycystic kidney disease (ARPKD). Cystin, the protein product of Cys1, is expressed in the primary apical cilia of renal ductal epithelial cells. In previous studies, we showed that cystin regulates Myc expression via interaction with the tumor suppressor, necdin. Here, we demonstrate rescue of the cpk renal phenotype by kidney-specific expression of a cystin-GFP fusion protein encoded by a transgene integrated into the Rosa26 locus. In addition, we show that expression of the cystin-GFP fusion protein in collecting duct cells downregulates expression of Myc in cpk kidneys. Finally, we report the first human patient with an ARPKD phenotype due to homozygosity for a predicted deleterious splicing defect in CYS1.These findings suggest that mutations in the Cys1 mouse and CYS1 human orthologues cause an ARPKD phenotype that is driven by overexpression of the Myc proto-oncogene. Translational Statement:The cystin-deficient cpk mouse is a model for the study of autosomal recessive polycystic kidney disease (ARPKD). We show that the cpk mouse phenotype is associated with altered Myc expression. To date, the clinical relevance of cystin deficiency to human disease was unclear, due to the absence of ARPKD cases associated with CYS1 mutations. We report the first case of ARPKD linked to a CYS1 mutation disrupting normal splicing. These findings confirm the relevance of cystin deficiency to human ARPKD, implicate Myc in disease initiation or progression, and validate the cpk mouse as a translationally relevant disease model.

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Glycogen synthase kinase-3β promotes cyst expansion in polycystic kidney disease

Cited by 44 publications

References 72 publications

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

The β isoform of GSK3 mediates podocyte autonomous injury in proteinuric glomerulopathy

Integrin-Linked Kinase Signaling Promotes Cyst Growth and Fibrosis in Polycystic Kidney Disease

Cystin gene mutations cause autosomal recessive polycystic kidney disease associated with alteredMycexpression

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