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Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease.

Abstract
Neutrophil gelatinase-associated lipocalin (Ngal) is a biomarker for acute and chronic renal injuries, including polycystic kidney disease (PKD). However, the effect of Ngal on PKD progression remains unexplored. To study this, we generated 3 strains of mice with different expression levels of Ngal within an established PKD model (Pkd1L3/L3): Pkd1L3/L3 (with endogenous Ngal), Pkd1L3/L3; NgalTg/Tg (with endogenous and overexpression of exogenous kidney-specific Ngal) and Pkd1L3/L3; Ngal-/- mice (with Ngal deficiency). Knockout of endogenous Ngal had no effect on phenotypes, cystic progression, or survival of the PKD mice. However, the transgenic mice had a significantly longer lifespan, smaller (but not fewer) renal cysts, and less interstitial fibrosis than the mice without or with endogenous Ngal. Western-blot analyses showed significant increases in Ngal and cleaved caspase-3 and decreases in α-smooth muscle actin, hypoxia-inducible factor 1-α, pro-caspase 3, proliferating cell nuclear antigen, Akt, mammalian target of rapamycin, and S6 Kinase in the transgenic mice as compared with the other 2 strains of PKD mice. Thus, overexpression of exogenous kidney-specific Ngal reduced cystic progression and prolonged the lifespan in PKD mice, was associated with reductions in interstitial fibrosis and proliferation, and augmented apoptosis.
AuthorsEllian Wang, Yuan-Yow Chiou, Wen-Yih Jeng, Hsiu-Kuan Lin, Hsi-Hui Lin, Hsian-Jean Chin, Chi-Kuang Leo Wang, Shang-Shiuan Yu, Shih-Chieh Tsai, Chih-Ying Chiang, Po-Hao Cheng, Hong-Jie Lin, Si-Tse Jiang, Sou-Tyau Chiu, Hsiu Mei Hsieh-Li
JournalKidney international (Kidney Int) Vol. 91 Issue 2 Pg. 412-422 (02 2017) ISSN: 1523-1755 [Electronic] United States
PMID28341240 (Publication Type: Comparative Study, Journal Article)
CopyrightCopyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Actins
  • Cadherins
  • Cdh16 protein, mouse
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Lipocalin-2
  • Proliferating Cell Nuclear Antigen
  • TRPP Cation Channels
  • alpha-smooth muscle actin, mouse
  • polycystic kidney disease 1 protein
  • Lcn2 protein, mouse
  • mTOR protein, mouse
  • EGFR protein, mouse
  • ErbB Receptors
  • Ribosomal Protein S6 Kinases
  • TOR Serine-Threonine Kinases
  • Casp3 protein, mouse
  • Caspase 3
Topics
  • Actins (metabolism)
  • Animals
  • Apoptosis
  • Cadherins (genetics)
  • Caspase 3 (metabolism)
  • Cell Proliferation
  • Disease Models, Animal
  • Disease Progression
  • ErbB Receptors (metabolism)
  • Female
  • Fibrosis
  • Genetic Predisposition to Disease
  • Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
  • Kidney (metabolism, pathology)
  • Lipocalin-2 (genetics, metabolism)
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phenotype
  • Phosphorylation
  • Polycystic Kidney Diseases (genetics, metabolism, pathology)
  • Proliferating Cell Nuclear Antigen (metabolism)
  • Promoter Regions, Genetic
  • Ribosomal Protein S6 Kinases (metabolism)
  • Signal Transduction
  • TOR Serine-Threonine Kinases (metabolism)
  • TRPP Cation Channels (genetics, metabolism)
  • Time Factors

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