Progressive renal distortion by multiple cysts in transgenic mice expressing artificial micrornas against PKD1

Ellian Wang, Hsiu Mei Hsieh, Yuan Yow Chiou, Yi Lin Chien, Hua Hui Ho, Hsian Jean Chin, Chi Kuang Leo Wang, San Chi Liang, Si Tse Jiang

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening inherited diseases, and the PKD1 gene is responsible for most cases of this disease. Previous efforts to establish a mouse model that recapitulates the phenotypic characteristics of ADPKD, which have used conventional or conditional knockout of the mouse orthologue Pkd1, have been unsuccessful or unreliable. In a previous study, we described the generation of a novel Pkd1 hypomorphic allele, in which Pkd1 expression was significantly reduced but not totally blocked. These Pkd1 homozygous mutant mice rapidly developed renal cystic disease, supporting the hypothesis that 'haploinsufficiency' explains development of the ADPKD phenotype. In the present study, we further investigated the Pkd1 haploinsufficiency effect by generating Pkd1 knockdown transgenic mice with co-cistronic expression of two miRNA hairpins specific to Pkd1 transcript and an Emerald GFP reporter driven by a human ubiquitin B promoter. Two transgenic lines which had ∼60-70% reduction of Pkd1 expression developed severe renal cystic disease at a rate similar to that of human ADPKD. These results further support the haploinsufficiency hypothesis, and suggest that the onset and progression of the renal cystic diseases are correlated with the level of Pkd1 expression. The two novel mutant lines of mice appear to be ideal models for the study of ADPKD.

Original languageEnglish
Pages (from-to)238-248
Number of pages11
JournalJournal of Pathology
Volume222
Issue number3
DOIs
Publication statusPublished - 2010 Jan 1

Fingerprint

Autosomal Dominant Polycystic Kidney
MicroRNAs
Transgenic Mice
Cysts
Cystic Kidney Diseases
Haploinsufficiency
Kidney
Knockout Mice
Alleles
Phenotype
Genes

Keywords

  • ADPKD
  • Knockdown
  • MicroRNA
  • Pkd1, haploinsufficiency

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Progressive renal distortion by multiple cysts in transgenic mice expressing artificial micrornas against PKD1. / Wang, Ellian; Hsieh, Hsiu Mei; Chiou, Yuan Yow; Chien, Yi Lin; Ho, Hua Hui; Chin, Hsian Jean; Wang, Chi Kuang Leo; Liang, San Chi; Jiang, Si Tse.

In: Journal of Pathology, Vol. 222, No. 3, 01.01.2010, p. 238-248.

Research output: Contribution to journalArticle

Wang, E, Hsieh, HM, Chiou, YY, Chien, YL, Ho, HH, Chin, HJ, Wang, CKL, Liang, SC & Jiang, ST 2010, 'Progressive renal distortion by multiple cysts in transgenic mice expressing artificial micrornas against PKD1', Journal of Pathology, vol. 222, no. 3, pp. 238-248. https://doi.org/10.1002/path.2765
Wang, Ellian ; Hsieh, Hsiu Mei ; Chiou, Yuan Yow ; Chien, Yi Lin ; Ho, Hua Hui ; Chin, Hsian Jean ; Wang, Chi Kuang Leo ; Liang, San Chi ; Jiang, Si Tse. / Progressive renal distortion by multiple cysts in transgenic mice expressing artificial micrornas against PKD1. In: Journal of Pathology. 2010 ; Vol. 222, No. 3. pp. 238-248.
@article{bab990559a184ab985e84014f414dd08,
title = "Progressive renal distortion by multiple cysts in transgenic mice expressing artificial micrornas against PKD1",
abstract = "Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening inherited diseases, and the PKD1 gene is responsible for most cases of this disease. Previous efforts to establish a mouse model that recapitulates the phenotypic characteristics of ADPKD, which have used conventional or conditional knockout of the mouse orthologue Pkd1, have been unsuccessful or unreliable. In a previous study, we described the generation of a novel Pkd1 hypomorphic allele, in which Pkd1 expression was significantly reduced but not totally blocked. These Pkd1 homozygous mutant mice rapidly developed renal cystic disease, supporting the hypothesis that 'haploinsufficiency' explains development of the ADPKD phenotype. In the present study, we further investigated the Pkd1 haploinsufficiency effect by generating Pkd1 knockdown transgenic mice with co-cistronic expression of two miRNA hairpins specific to Pkd1 transcript and an Emerald GFP reporter driven by a human ubiquitin B promoter. Two transgenic lines which had ∼60-70{\%} reduction of Pkd1 expression developed severe renal cystic disease at a rate similar to that of human ADPKD. These results further support the haploinsufficiency hypothesis, and suggest that the onset and progression of the renal cystic diseases are correlated with the level of Pkd1 expression. The two novel mutant lines of mice appear to be ideal models for the study of ADPKD.",
keywords = "ADPKD, Knockdown, MicroRNA, Pkd1, haploinsufficiency",
author = "Ellian Wang and Hsieh, {Hsiu Mei} and Chiou, {Yuan Yow} and Chien, {Yi Lin} and Ho, {Hua Hui} and Chin, {Hsian Jean} and Wang, {Chi Kuang Leo} and Liang, {San Chi} and Jiang, {Si Tse}",
year = "2010",
month = "1",
day = "1",
doi = "10.1002/path.2765",
language = "English",
volume = "222",
pages = "238--248",
journal = "Journal of Pathology",
issn = "0022-3417",
publisher = "John Wiley and Sons Ltd",
number = "3",

}

TY - JOUR

T1 - Progressive renal distortion by multiple cysts in transgenic mice expressing artificial micrornas against PKD1

AU - Wang, Ellian

AU - Hsieh, Hsiu Mei

AU - Chiou, Yuan Yow

AU - Chien, Yi Lin

AU - Ho, Hua Hui

AU - Chin, Hsian Jean

AU - Wang, Chi Kuang Leo

AU - Liang, San Chi

AU - Jiang, Si Tse

PY - 2010/1/1

Y1 - 2010/1/1

N2 - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening inherited diseases, and the PKD1 gene is responsible for most cases of this disease. Previous efforts to establish a mouse model that recapitulates the phenotypic characteristics of ADPKD, which have used conventional or conditional knockout of the mouse orthologue Pkd1, have been unsuccessful or unreliable. In a previous study, we described the generation of a novel Pkd1 hypomorphic allele, in which Pkd1 expression was significantly reduced but not totally blocked. These Pkd1 homozygous mutant mice rapidly developed renal cystic disease, supporting the hypothesis that 'haploinsufficiency' explains development of the ADPKD phenotype. In the present study, we further investigated the Pkd1 haploinsufficiency effect by generating Pkd1 knockdown transgenic mice with co-cistronic expression of two miRNA hairpins specific to Pkd1 transcript and an Emerald GFP reporter driven by a human ubiquitin B promoter. Two transgenic lines which had ∼60-70% reduction of Pkd1 expression developed severe renal cystic disease at a rate similar to that of human ADPKD. These results further support the haploinsufficiency hypothesis, and suggest that the onset and progression of the renal cystic diseases are correlated with the level of Pkd1 expression. The two novel mutant lines of mice appear to be ideal models for the study of ADPKD.

AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common life-threatening inherited diseases, and the PKD1 gene is responsible for most cases of this disease. Previous efforts to establish a mouse model that recapitulates the phenotypic characteristics of ADPKD, which have used conventional or conditional knockout of the mouse orthologue Pkd1, have been unsuccessful or unreliable. In a previous study, we described the generation of a novel Pkd1 hypomorphic allele, in which Pkd1 expression was significantly reduced but not totally blocked. These Pkd1 homozygous mutant mice rapidly developed renal cystic disease, supporting the hypothesis that 'haploinsufficiency' explains development of the ADPKD phenotype. In the present study, we further investigated the Pkd1 haploinsufficiency effect by generating Pkd1 knockdown transgenic mice with co-cistronic expression of two miRNA hairpins specific to Pkd1 transcript and an Emerald GFP reporter driven by a human ubiquitin B promoter. Two transgenic lines which had ∼60-70% reduction of Pkd1 expression developed severe renal cystic disease at a rate similar to that of human ADPKD. These results further support the haploinsufficiency hypothesis, and suggest that the onset and progression of the renal cystic diseases are correlated with the level of Pkd1 expression. The two novel mutant lines of mice appear to be ideal models for the study of ADPKD.

KW - ADPKD

KW - Knockdown

KW - MicroRNA

KW - Pkd1, haploinsufficiency

UR - http://www.scopus.com/inward/record.url?scp=77958016655&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77958016655&partnerID=8YFLogxK

U2 - 10.1002/path.2765

DO - 10.1002/path.2765

M3 - Article

VL - 222

SP - 238

EP - 248

JO - Journal of Pathology

JF - Journal of Pathology

SN - 0022-3417

IS - 3

ER -