Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common renal genetic disorder, however it still lacks a cure. The discovery of new therapies heavily depends on understanding key signalling pathways that lead to ADPKD. The JAnus Kinase and Signal Transducers and Activators of Transcription (JAK/STAT) pathway is aberrantly activated and contributes to ADPKD pathogenesis via enhancing epithelial proliferation. Yet the mechanisms underlying the upregulation of JAK/STAT activity in this disease context is completely unknown. Here, we investigate the role of JAK2 in ADPKD using a murine model of ADPKD (Pkd1nl/nl). In normal kidneys, JAK2 expression is limited to tubular epithelial and vascular cells with lesser staining in bowman’s capsule and remains below detection level in the interstitium. By contrast, in kidneys of mice with ADPKD, JAK2 is higher in cyst-lining cells when compared to normal tubules and critically, it is ectopically expressed in the interstitium, suggesting that ectopic JAK2 may contribute to ADPKD. JAK2 activity was inhibited using either curcumin, a natural compound with strong JAK2 inhibitor activity, or Tofacitinib, a clinically used selective JAK small molecule inhibitor. JAK2 inhibition led to significantly reduced tyrosine phosphorylation of STAT3 and markedly reduced cystic growth of human and mouse ADPKD-derived cells in cystogenesis assays. Taken together, our results indicate that blockade of JAK2 shows promise as a novel therapeutic target in ADPKD.
Highlights
Autosomal dominant polycystic kidney disease (ADPKD) is a devastating multi-organ disease lacking a cure
We found that JAK2 is diffusely expressed by cortical renal epithelial cells and its expression appears predominately cytoplasmic with no detectable expression by fibroblasts or the interstitium (Fig. 1A and A’)
We show that JAK2 levels are higher in polycystic when compared with wild-type kidneys a finding that may be therapeutically relevant given that we identified that JAK blockade, using either curcumin or a selective JAK inhibitor, potently reduces cystic growth in human ADPKD-derived lines
Summary
Autosomal dominant polycystic kidney disease (ADPKD) is a devastating multi-organ disease lacking a cure. Patients with ADPKD exhibit a vascular phenotype, presenting with hypertension and aneurysms[1,2] which together with cysts in kidneys and other organs, shows that ADPKD is a systemic disease. STAT transcription factors become activated by a series of phosphorylation events on conserved tyrosine residues facilitated by one of four JAK kinases, namely JAK1-JAK3 or Tyk[2]. Because of their involvement in disease, JAK small-molecule inhibitors have been developed, including the approved Tofacitinib, Ruxolitinib, and Baracitinib[12,13,14,15]. We investigated the expression of JAK2 in kidneys of mice with and without ADPKD and inhibited JAK2 activity to examine its role in cystogenesis
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