Signal transducer and activator of transcription-6 (STAT6) inhibition suppresses renal cyst growth in polycystic kidney disease

Abstract

Autosomal-dominant (AD) polycystic kidney disease (PKD) is a leading cause of renal failure in the United States, and currently lacks available treatment options to slow disease progression. Mutations in the gene coding for polycystin-1 (PC1) underlie the majority of cases but the function of PC1 has remained poorly understood. We have previously shown that PC1 regulates the transcriptional activity of signal transducer and activator of transcription-6 (STAT6). Here we show that STAT6 is aberrantly activated in cyst-lining cells in PKD mouse models. Activation of the STAT6 pathway leads to a positive feedback loop involving auto/ paracrine signaling by IL13 and the IL4/13 receptor. The presence of IL13 in cyst fluid and the overexpression of IL4/13 receptor chains suggests a mechanism of sustained STAT6 activation in cysts. Genetic inactivation of STAT6 in a PKD mouse model leads to significant inhibition of proliferation and cyst growth and preservation of renal function. We show that the active metabolite of leflunomide, a drug approved for treatment of arthritis, inhibits STAT6 in renal epithelial cells. Treatment of PKD mice with this drug leads to amelioration of the renal cystic disease similar to genetic STAT6 inactivation. These results suggest STAT6 as a promising drug target for treatment of ADPKD.signal transduction | cytokines | preclinical

Exploitation of the Polymeric Immunoglobulin Receptor for Antibody Targeting to Renal Cyst Lumens in Polycystic Kidney Disease

“…into the SC-We found previously that STAT6 is aberrantly activated in renal cyst-lining epithelial cells in two mouse models of PKD, the Bpk model and the human-orthologous Pkd1 cond/cond :Nestin cre model (12). In addition, significant amounts of the STAT6 activating cytokine IL13 are present in cyst fluid in these models (12).…”

“…Ϫ/Ϫ animals on a BALB/c background were obtained from The Jackson Laboratory (Bar Harbor, ME) and crossed with the WT/bpk animals as described previously (12).…”

“…Previous work from our laboratory has indicated that PC1 can regulate the activity of the transcription factor STAT6 (11) and that aberrant activation of the STAT6 pathway contributes to renal cyst growth (12). STAT6 is typically activated by the cytokines IL4 or IL13, which bind to the heterodimeric IL4/13 receptor (13).…”

“…Our results indicated that activation of STAT6 in cyst-lining cells causes a positive feedback loop involving the secretion of IL13 into cyst fluid and IL4/IL13 receptor activation at apical membranes of cyst-lining epithelial cells. Gene ablation of STAT6 or use of the pharmacological inhibitor leflunomide lead to reduced renal cyst growth in a PKD mouse model (12).…”

Present Status and Advances in Autosomal Dominant Polycystic Kidney Disease

“…These results demonstrated that the STAT3 signaling pathway is regulated by PC1 and serve as a driver of renal epithelial proliferation during normal kidney development and renal cyst growth. Studies have shown that inhibition of STAT6 by leflunomide (LEF) slows cyst growth in ADPKD mouse models [81].…”