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

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) arises primarily due to Pkd1 mutations and is characterised by increased kidney epithelial proliferation. The Janus Kinase and Signal Transducers and Activators of Transcription (JAK-STAT) is a proliferation regulating pathway implicated in ADPKD. Curcumin, an anti-inflammatory phytochemical, has been shown to limit murine cystogenesis possibly via JAK-STAT. However, the mechanisms employed by curcumin to inhibit JAK-STAT are uncertain. We treated ADPKD-derived renal epithelial cells with curcumin at different concentrations over 9 days and studied their growth in organotypic cystforming assays. Curcumin potently blocked cystic growth in human and mouse renal epithelial cells without requiring any additional cell types, suggesting a direct effect on kidney epithelial cells. The level of tyrosine phosphorylated-STAT3 was reduced within 1 hour of curcumin treatment in a dose-dependent manner. While total STAT3 protein levels remained unaltered, suggesting that curcumin reduces phosphorylation of STAT3 possibly via JAK2, a tyrosine kinase upstream of STAT3. Mechanistically, curcumin caused JAK2 to move into an insoluble fraction, without causing JAK2 proteosomal-degradation. Instead curcumin led to JAK2 to accumulate into aggresomes, which are known depots for inactivated enzymes. We studied JAK2 expression in kidneys of the Pkd1 nl/nl mice, which spontaneously develop progressive ADPKD. JAK2 was highly expressed in cyst-lining renal epithelial cells at 5 and 10 weeks of age, suggesting a potential role in ADPKD pathophysiology. Collectively, these data suggest that curcumin reduces STAT3 signalling and cystic growth by inactivating JAK2, thus selective JAK2 inhibition may be of therapeutic benefit in ADPKD.