|Title||Identification of Targets of Interleukin-13 and Signal Transducer and Activator of Transcription-6 (STAT6) Signaling in Polycystic Kidney Disease.|
|Publication Type||Journal Article|
|Year of Publication||2018|
|Authors||Olsan, EE, West, JD, Torres, JA, Doerr, N, Weimbs, T|
|Journal||Am J Physiol Renal Physiol|
|Date Published||2018 Mar 07|
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 C-terminal cleavage fragment of PC1, PC1-p30, that 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 interleukin-13 (IL13), a STAT6 activating cytokine, are found in the cyst fluid of PKD mouse models and increased IL13 receptors in ADPKD patient tissue suggesting that a positive feedback loop between IL13 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 IL13/STAT6 signaling may contribute to PKD progression. We demonstrate that the expression of periostin, galectin-3 and interleukin-24 (IL24) are up regulated in various forms of PKD and that their aberrant regulation is mediated by IL13 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 IL13 treatment in kidney epithelial cells, that galectin-3 expression is increased after injecting IL13 in vivo, and that IL24 expression is upregulated by both IL13 treatment and PC1-p30 over expression in mouse and human kidney cells. Overall, these findings provide insight into the possible mechanisms by which increased IL13/STAT6 signaling contributes to PKD progression and suggest potential therapeutic targets.
|Alternate Journal||Am. J. Physiol. Renal Physiol.|