Growth hormone inhibition in Autosomal Dominant Polycystic Kidney Disease

Relevance: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disease worldwide and the primary genetic cause of end stage- renal failure. ADPKD is characterised by progressive renal hypertrophy and development of renal cysts, leading to loss of function and renal failure requiring dialysis and transplant. There are currently no curative treatments and only one drug (Tolvaptan) available on the market that delays progression of disease which not all people with ADPKD are eligible to take. Rationale & Hypothesis: Aberrant signalling in the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway has been implicated in ADPKD pathogenesis and progression, and our laboratory has previously found aberrant activation of JAK2 and STAT5 signalling alongside elevated circulating growth hormone (GH) in a mouse model of ADPKD. This project investigates the hypothesis that growth hormone-induced JAK2/STAT5 signalling promotes proliferation and subsequent cystogenesis in ADPKD and that inhibition of this pathway may slow progression of disease. Results: Recombinant GH and GH with a mutation resulting in a dominant negative GH receptor antagonist (GHA) were successfully expressed and their ability to modulate STAT5 activity was demonstrated in kidney cells. Stimulation of human and mouse cellular models of ADPKD with GH significantly increases STAT5 activation and expression of STAT5 transcriptional targets, which is significantly reduced with treatment with GHA or the JAK inhibitor Ruxolitinib. This study presents the novel finding that growth hormone elevates cyst expansion and proliferation in cellular models of ADPKD, and inhibition of GH-JAK2-STAT5 signalling with GHA, Ruxolitinib or genetic knockdown abrogates GH-driven cystic growth and proliferation. In vivo, Ruxolitinib treatment protects renal function and reduces renal hypertrophy and fibrosis in a mouse model of ADPKD. Conclusion: This thesis identifies that growth hormone promotes proliferation and cyst expansion of cystic cells via JAK2-STAT5 signalling. Inhibition of GH-JAK2-STAT5 is beneficial in reducing proliferation, cystic growth and improving renal function.