Kidney Week

Abstract: TH-PO462

Targeting Growth Hormone/JAK2 Signaling as a Novel Therapy for Polycystic Kidney Disease Treatment

Session Information

• Cystic Kidney Diseases: Clinical Assessment and Therapeutic Directions
  October 24, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Macleod, Fiona, Queen Mary University of London Faculty of Medicine and Dentistry, London, London, United Kingdom

Fiona Macleod

• Fragiadaki, Maria, Queen Mary University of London Faculty of Medicine and Dentistry, London, London, United Kingdom

Maria Fragiadaki, PhD

Group or Team Name

• Maria Fragiadaki Lab.

Background

PKD is characterized by renal cyst growth, fibrosis, and renal failure due to mutations in PKD1 or PKD2, leading to dysregulated JAK/STAT signaling. Our previous studies have shown elevated Growth Hormone (GH) levels and excessive JAK2/STAT5 activation in ADPKD mouse models. This study explores the therapeutic potential of targeting the GH/JAK/STAT pathway in ADPKD.

Methods

We conducted cystogenesis and proliferation assays in human cells. We employed three strategies to antagonise GH/JAK2 signaling: (i) GH receptor antagonist (GHA), (ii) ruxolitinib (a small molecule JAK2 inhibitor), and (iii) siRNA-mediated silencing of GHR/STAT5. Proliferation was measured by flow cytometry and qPCR. Ruxolitinib or vehicle control was administered to Pkd1^nl/nl mice (n=20), and kidney function, fibrosis, inflammation and RNA-seq analyses were performed. GH and IGF-1 levels were measured by ELISA and GH receptor levels determined by immunohistochemistry.

Results

GH levels were elevated (~3-fold, P<0.01) in Pkd1^nl/nl mice. GH receptor (GHR) was expressed in renal cyst-derived human cells and murine Pkd1^nl/nl kidneys. RNA-seq analysis revealed that GH induces proliferation via mitogenic factors, including a ~4-fold increase in cyclin D1 expression (P<0.0001). GH stimulated significant increases in cell cycle progression and mitosis (P<0.01). Critically, ruxolitinib or GHA effectively countered GH-induced proliferation, inflammation, and STAT5 transcriptional activity (Ruxo-P<0.05; GHA-P<0.001) in renal cells. GH enhanced cyst growth in vitro, an effect fully antagonised by ruxolitinib, GHA, or GHR/STAT5 siRNA. In vivo, ruxolitinib treatment (50mg/kg) significantly reduced phosphorylation and activity of JAK2, which in turn led to improved renal function (P<0.05), reduced kidney size (P<0.05), and decreased fibrosis (P<0.01). Bulk-RNA-seq coupled with spatial transcriptomics revealed the transcriptome changes responsible for the anti-fibrotic and anti-proliferative properties of ruxolitinib treatment.

Conclusion

Our findings demonstrate the therapeutic potential of GH/GHR/JAK2/STAT5 antagonism in experimental ADPKD. Antagonizing JAK2 signaling leads to decreased fibrosis and improved renal function. We propose JAK2 antagonism as a promising strategy to decelerate the progression of ADPKD. These findings have implication for additional renal diseases characterised by fibrosis.

Funding

• Government Support – Non-U.S.