JAK2 is highly expressed by cyst-lining cells and regulates cystogenesis.

Abstract

Dysregulated JAK/STAT signalling is implicated in polycystic kidney disease, which is a common genetic disease leading to renal failure. However, the mechanisms underlying JAK/STAT-mediated cystogenesis arepoorlyunderstood.TheroleofJAK2wasinvestigated immunohistochemically in a murine model of cystic disease (Pkd1nl/nl). In the normal kidney, JAK2 is restricted to tubular epithelial and vascular cells with lesser staining in bowmans capsule and is undetectable in the interstitium. By contrast, in the diseased kidney JAK2 appears stronger in cyst-lining cells when compared to normal tubules and appears mislocalised in the interstitium. Given that JAK2 is a major tyrosine kinase activating JAK/STAT, we considered whether its inhibition can attenuate cystic growth in vitro. To assess this we used curcumin, a natural phytochemical, which significantly reduced JAK2 levels and STAT3 activity. Consistently, reduced JAK2/STAT3 activity was correlated with reduced cystic growth of cystic cells in three-dimensional cyst assays. Taken together, our results suggest that JAK2 is a key signalling molecule that functions to inhibit cystic growth in cystic tubular epithelial cells, thus providing the foundation for its development as a novel therapeutic in polycystic kidney disease.