Dataset Information

Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is a common kidney disease caused by mutations in PKD1 or PKD2. Metformin reduces cyst growth in mouse models of PKD1. However, metformin has not been studied in animal models of PKD2, and the cellular mechanism underlying its effectiveness is not entirely clear. This study investigated the effects of metformin on cyst formation in a zebrafish model of polycystin-2 deficiency resulting from morpholino knockdown of pkd2. We added metformin (2.5 to 20?mM) to the embryo media between 4 and 48?hours post fertilisation and observed pronephric cyst formation by using the wt1b promoter-driven GFP signal in Tg(wt1b:GFP) pkd2 morphants. Metformin inhibited pronephric cyst formation by 42-61% compared with the untreated controls. Metformin also reduced the number of proliferating cells in the pronephric ducts, the degree of dorsal body curvature, and the infiltration of leukocytes surrounding the pronephros. Moreover, metformin treatment increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and enhanced autophagy in the pronephros. Our data suggest that metformin reduces cyst formation through activation of the AMPK pathway and modulation of defective cellular events such as proliferation and autophagy. These results also imply that metformin could have therapeutic potential for ADPKD treatment.

SUBMITTER: Chang MY

PROVIDER: S-EPMC5541071 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency.

Chang Ming-Yang MY Ma Tsu-Lin TL Hung Cheng-Chieh CC Tian Ya-Chung YC Chen Yung-Chang YC Yang Chih-Wei CW Cheng Yi-Chuan YC

Scientific reports 20170802 1

Autosomal dominant polycystic kidney disease (ADPKD) is a common kidney disease caused by mutations in PKD1 or PKD2. Metformin reduces cyst growth in mouse models of PKD1. However, metformin has not been studied in animal models of PKD2, and the cellular mechanism underlying its effectiveness is not entirely clear. This study investigated the effects of metformin on cyst formation in a zebrafish model of polycystin-2 deficiency resulting from morpholino knockdown of pkd2. We added metformin (2.5 ...[more]

PMID: 28769124

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Project description:Embryonic axis formation in vertebrates is initiated by the establishment of the dorsal Nieuwkoop blastula organizer, marked by the nuclear accumulation of maternal ?-catenin, a transcriptional effector of canonical Wnt signaling. Known regulators of axis specification include the canonical Wnt pathway components that positively or negatively affect ?-catenin. An involvement of G-protein coupled receptors (GPCRs) was hypothesized from experiments implicating G proteins and intracellular calcium in axis formation, but such GPCRs have not been identified. Mobilization of intracellular Ca(2+) stores generates Ca(2+) transients in the superficial blastomeres of zebrafish blastulae when the nuclear accumulation of maternal ?-catenin marks the formation of the Nieuwkoop organizer. Moreover, intracellular Ca(2+) downstream of non-canonical Wnt ligands was proposed to inhibit ?-catenin and axis formation, but mechanisms remain unclear. Here we report a novel function of Ccr7 GPCR and its chemokine ligand Ccl19.1, previously implicated in chemotaxis and other responses of dendritic cells in mammals, as negative regulators of ?-catenin and axis formation in zebrafish. We show that interference with the maternally and ubiquitously expressed zebrafish Ccr7 or Ccl19.1 expands the blastula organizer and the dorsoanterior tissues at the expense of the ventroposterior ones. Conversely, Ccr7 or Ccl19.1 overexpression limits axis formation. Epistatic analyses demonstrate that Ccr7 acts downstream of Ccl19.1 ligand and upstream of ?-catenin transcriptional targets. Moreover, Ccl19/Ccr7 signaling reduces the level and nuclear accumulation of maternal ?-catenin and its axis-inducing activity and can also inhibit the Gsk3? -insensitive form of ?-catenin. Mutational and pharmacologic experiments reveal that Ccr7 functions during axis formation as a GPCR to inhibit ?-catenin, likely by promoting Ca(2+) transients throughout the blastula. Our study delineates a novel negative, Gsk3?-independent control mechanism of ?-catenin and implicates Ccr7 as a long-hypothesized GPCR regulating vertebrate axis formation.

Dataset Information

Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency.

Publications

Metformin Inhibits Cyst Formation in a Zebrafish Model of Polycystin-2 Deficiency.

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