Aberrant Cellular Pathways in PKD

Grazioli, Alison; Outeda, Patricia; Watnick, Terry

doi:10.1007/978-1-4939-7784-0_4

Cited by 1 publication

(2 citation statements)

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“…The MAPK/ERK pathway has been suggested to be involved in cyst growth by affecting cell proliferation. [22][23][24] The activation of receptors, including receptor tyrosine kinases, GPCRs, and integrins, could lead to the phosphorylation of MAPK/ ERK. The phosphorylated ERK would then activate various transcriptional factors, including c-Myc, c-Fos, and Foxm1.…”

Section: Discussionmentioning

confidence: 99%

“…9,[18][19][20][21] Multiple signaling pathways, including mTOR, MAPK/ERK, and cAMP-dependent pathways, have been suggested to regulate cyst growth at least in part by altering cell proliferation. [22][23][24] In this study, we used transcriptional profiling in adult mouse kidneys at a stage before cyst formation to identify the earliest in vivo transcriptional changes that follow inactivation of polycystins. To identify CDCA-related transcriptional responses specific to cyst-forming cells, we compared three groups of kidney-specific knockout mice: Pkd2 single mutants destined to form cysts and Ift88/Pkd2 double mutants and nonknockout controls, which are protected from cyst progression.…”

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confidence: 99%

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Cyclin-Dependent Kinase 1 Activity Is a Driver of Cyst Growth in Polycystic Kidney Disease

Zhang

Balbo

et al. 2020

JASN

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BackgroundMutations in PKD1 and PKD2, which encode the transmembrane proteins polycystin-1 and polycystin-2, respectively, cause autosomal dominant polycystic kidney disease (ADPKD). Polycystins are expressed in the primary cilium, and disrupting cilia structure significantly slows ADPKD progression following inactivation of polycystins. The cellular mechanisms of polycystin- and cilia-dependent cyst progression in ADPKD remain incompletely understood.MethodsUnbiased transcriptional profiling in an adult-onset Pkd2 mouse model before cysts formed revealed significant differentially expressed genes (DEGs) in Pkd2 single-knockout kidneys, which were used to identify candidate pathways dysregulated in kidneys destined to form cysts. In vivo studies validated the role of the candidate pathway in the progression of ADPKD. Wild-type and Pkd2/Ift88 double-knockout mice that are protected from cyst growth served as controls.ResultsThe RNASeq data identified cell proliferation as the most dysregulated pathway, with 15 of 241 DEGs related to cell cycle functions. Cdk1 appeared as a central component in this analysis. Cdk1 expression was similarly dysregulated in Pkd1 models of ADPKD, and conditional inactivation of Cdk1 with Pkd1 markedly improved the cystic phenotype and kidney function compared with inactivation of Pkd1 alone. The Pkd1/Cdk1 double knockout blocked cyst cell proliferation that otherwise accompanied Pkd1 inactivation alone.ConclusionsDysregulation of Cdk1 is an early driver of cyst cell proliferation in ADPKD due to Pkd1 inactivation. Selective targeting of cyst cell proliferation is an effective means of slowing ADPKD progression caused by inactivation of Pkd1.

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Section: Discussionmentioning

confidence: 99%