STAT5 drives abnormal proliferation in autosomal dominant polycystic kidney disease

Kidney Int. 2017 Mar;91(3):575-586. doi: 10.1016/j.kint.2016.10.039. Epub 2017 Jan 16.


Autosomal dominant polycystic kidney disease (ADPKD) leads to renal failure. The hallmark of ADPKD is increased epithelial proliferation, which has been proposed to be due to atypical signaling including abnormal JAK-STAT activity. However, the relative contribution of JAK-STAT family members in promoting proliferation in ADPKD is unknown. Here, we present siRNA JAK-STAT-focused screens discovering a previously unknown proliferative role for multiple JAK-STAT components (including STAT1, STAT2, STAT4, STAT5a, and STAT5b). Amongst these, we selected to study the growth hormone/growth hormone receptor/STAT5-axis because of its known role as a regulator of growth in nonrenal tissues. Loss of STAT5 function, facilitated by pharmacological inhibition or siRNAs, significantly reduced proliferation with an associated reduction in cyst growth in vitro. To study whether STAT5 is abnormally activated in vivo, we analyzed its expression using two independent mouse models of ADPKD. STAT5 was nuclear, thus activated, in renal epithelial cyst lining cells in both models. To test whether forced activation of STAT5 can modulate proliferation of renal cells in vivo, irrespective of the Pkd1 status, we overexpressed growth hormone. These mice showed increased STAT5 activity in renal epithelial cells, which correlated with de novo expression of cyclin D1, a STAT5 target gene. Chromatin immunoprecipitation experiments revealed that STAT5 transcriptionally activated cyclin D1 in a growth hormone-dependent fashion, thus providing a mechanism into how STAT5 enhances proliferation. Finally, we provide evidence of elevated serum growth hormone in Pkd1 mutant mice. Thus, the growth hormone/STAT5 signaling axis is a novel therapeutic target in ADPKD.

Keywords: ADPKD; cell signaling; cell survival; gene expression.

MeSH terms

  • Animals
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Nucleus / metabolism
  • Cell Proliferation* / drug effects
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Disease Models, Animal
  • Epithelial Cells / drug effects
  • Epithelial Cells / metabolism*
  • Epithelial Cells / pathology
  • Genotype
  • Growth Hormone / genetics
  • Growth Hormone / metabolism
  • Humans
  • Janus Kinases / antagonists & inhibitors
  • Janus Kinases / genetics
  • Janus Kinases / metabolism
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Mice, Transgenic
  • Phenotype
  • Polycystic Kidney, Autosomal Dominant / drug therapy
  • Polycystic Kidney, Autosomal Dominant / genetics
  • Polycystic Kidney, Autosomal Dominant / metabolism*
  • Polycystic Kidney, Autosomal Dominant / pathology
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • STAT5 Transcription Factor / antagonists & inhibitors
  • STAT5 Transcription Factor / genetics
  • STAT5 Transcription Factor / metabolism*
  • Signal Transduction
  • TRPP Cation Channels / genetics
  • TRPP Cation Channels / metabolism
  • Time Factors
  • Transfection
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*


  • CCND1 protein, human
  • Carrier Proteins
  • Protein Kinase Inhibitors
  • STAT5 Transcription Factor
  • STAT5A protein, human
  • STAT5B protein, human
  • Stat5a protein, mouse
  • Stat5b protein, mouse
  • TRPP Cation Channels
  • Tumor Suppressor Proteins
  • polycystic kidney disease 1 protein
  • Cyclin D1
  • Growth Hormone
  • Janus Kinases
  • somatotropin-binding protein