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Identification of targets of IL-13 and STAT6 signaling in polycystic kidney disease
- Source :
- American Journal of Physiology-Renal Physiology. 315:F86-F96
- Publication Year :
- 2018
- Publisher :
- American Physiological Society, 2018.
-
Abstract
- Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening, highly prevalent monogenic disease caused by mutations in polycystin-1 (PC1) in 85% of patients. We have previously identified a COOH-terminal cleavage fragment of PC1, PC1-p30, which interacts with the transcription factor STAT6 to promote transcription. STAT6 is aberrantly active in PKD mouse models and human ADPKD, and genetic removal or pharmacological inhibition of STAT6 attenuates disease progression. High levels of IL-13, a STAT6-activating cytokine, are found in the cyst fluid of PKD mouse models and increased IL-13 receptors in ADPKD patient tissue, suggesting that a positive feedback loop exists between IL-13 and STAT6 is activated in cystic epithelial cells and contributes to disease progression. In this study, we aimed to identify genes aberrantly regulated by STAT6 to better understand how increased IL-13/STAT6 signaling may contribute to PKD progression. We demonstrate that the expression of periostin, galectin-3, and IL-24 is upregulated in various forms of PKD and that their aberrant regulation is mediated by IL-13 and STAT6 activity. Periostin and galectin-3 have previously been implicated in PKD progression. We support these findings by showing that periostin expression is increased after IL-13 treatment in kidney epithelial cells, that galectin-3 expression is increased after injecting IL-13 in vivo and that IL-24 expression is upregulated by both IL-13 treatment and PC1-p30 overexpression in mouse and human kidney cells. Overall, these findings provide insight into the possible mechanisms by which increased IL-13/STAT6 signaling contributes to PKD progression and suggest potential therapeutic targets.
- Subjects :
- 0301 basic medicine
TRPP Cation Channels
Physiology
Galectin 3
Galectins
Autosomal dominant polycystic kidney disease
Monogenic disease
03 medical and health sciences
0302 clinical medicine
parasitic diseases
Polycystic kidney disease
medicine
Animals
Humans
Genetic Predisposition to Disease
Kidney Tubules, Collecting
STAT6
Mice, Knockout
Interleukin-13
integumentary system
business.industry
Interleukins
Blood Proteins
Polycystic Kidney, Autosomal Dominant
medicine.disease
Peptide Fragments
Mice, Inbred C57BL
Disease Models, Animal
HEK293 Cells
Phenotype
030104 developmental biology
030220 oncology & carcinogenesis
Interleukin 13
Immunology
Cytokines
Identification (biology)
STAT6 Transcription Factor
business
Cell Adhesion Molecules
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 15221466 and 1931857X
- Volume :
- 315
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Renal Physiology
- Accession number :
- edsair.doi.dedup.....1701c773f34c7b5ae203f95ee1c6d000