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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  JA nus  K inase and  S ignal  T ransducers and  A ctivators of  T ranscription (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 (Pkd1 nl/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.

Renal expression of JAK2 is high in polycystic kidney disease and its inhibition reduces cystogenesis