Overexpression of exogenous kidney-specific Ngal attenuates progressive cyst development and prolongs lifespan in a murine model of polycystic kidney disease.
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.
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan; Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan.
Ellian
E
Wang
Division of Pediatric Nephrology, Department of Pediatrics, Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, Tainan 701, Taiwan.
Yuan-Yow
YY
Chiou
University Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan; Department of Biochemistry and Molecular Biology, National Cheng Kung University, Tainan, Taiwan.
Wen-Yih
WY
Jeng
Department of Physiology, National Cheng-Kung University Medical College, Tainan, Taiwan.
Hsiu-Kuan
HK
Lin
Department of Physiology, National Cheng-Kung University Medical College, Tainan, Taiwan.
Hsi-Hui
HH
Lin
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan.
Hsian-Jean
HJ
Chin
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan.
Chi-Kuang
CK
Leo Wang
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Shang-Shiuan
SS
Yu
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan.
Shih-Chieh
SC
Tsai
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan.
Chih-Ying
CY
Chiang
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan.
Po-Hao
PH
Cheng
University Center for Bioscience and Biotechnology, National Cheng Kung University, Tainan, Taiwan.
Hong-Jie
HJ
Lin
Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Taipei and Tainan, Taiwan; Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address: stjiang@nlac.org.tw.
Si-Tse
ST
Jiang
Taipei Hospital, Ministry of Health and Welfare, New Taipei City, Taiwan. Electronic address: soutyauchiu@yahoo.com.tw.
Sou-Tyau
ST
Chiu
Department of Life Science, National Taiwan Normal University, Taipei, Taiwan. Electronic address: hmhsieh@ntnu.edu.tw.
Hsiu Mei
HM
Hsieh-Li
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D015820:Cadherins / Q000235:genetics; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D000071068:Lipocalin-2 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D010766:Phosphorylation; D007690:Polycystic Kidney Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D011401:Promoter Regions, Genetic; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D050396:TRPP Cation Channels / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D000199:Actins; D015820:Cadherins; D053148:Caspase 3; D066246:ErbB Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000071068:Lipocalin-2; D018809:Proliferating Cell Nuclear Antigen; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D050396:TRPP Cation Channels; C491946:Cdh16 protein, mouse; C497443:Hif1a protein, mouse; C544013:alpha-smooth muscle actin, mouse; C071332:Lcn2 protein, mouse; C546843:mTOR protein, mouse; C541485:EGFR protein, mouse; C505409:Casp3 protein, mouse
Pkd1; cysts; neutrophil gelatinase-associated lipocalin