Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a commonly inherited disorder mostly caused by mutations in PKD1, encoding polycystin-1 (PC1). The disease is characterized by development and growth of epithelium-lined cyst in both kidneys, often leading to renal failure. There is no specific treatment for this disease. Here, we report a sustained activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) in ischemic injured and uninjured Pkd1 knockout polycystic kidneys and in human ADPKD kidneys. Through a chemical library screen, we identified the anti-parasitic compound pyrimethamine as an inhibitor of STAT3 function. Treatment with pyrimethamine decreases cell proliferation in human ADPKD cells and blocks renal cyst formation in an adult and a neonatal PKD mouse model. Moreover, we demonstrated that a specific STAT3 inhibitor, S3I-201, reduces cyst formation and growth in a neonatal PKD mouse model. Our results suggest that PC1 acts as a negative regulator of STAT3 and that blocking STAT3 signaling with pyrimethamine or similar drugs may be an attractive therapy for human ADPKD.

The Cleaved Cytoplasmic Tail of Polycystin-1 Regulates Src-Dependent STAT3 Activation

“…Previous findings by us 4 and others 7,8 have demonstrated that STAT3 is strongly activated in renal cyst-lining cells in human ADPKD and several PKD mouse models, and suggested that STAT3 is a driving force for cyst growth. 9,11 However, the mechanism of STAT3 activation in renal cysts remained unknown.…”

“…Altogether, these results suggest that the high levels of cAMP and SOCS3 in renal cystic cells should be expected to suppress JAK-dependent activation of STAT3. However, because STAT3 is clearly strongly activated in PKD, 4,7,8 this suggests that STAT3 activation in PKD is mediated by a JAK-independent pathway. To directly test this, we investigated the levels of activated JAK2 (P-Tyr 1007/1008 ) in two PKD mouse models.…”

“…4 We and others have shown that STAT3 is very strongly activated by tyrosine-phosphorylation in cyst-lining cells in ADPKD and several mouse models. 4,7,8 Moreover, initial attempts to inhibit STAT3 in PKD mouse models have led to reduction of renal cyst growth. 7,8 These results suggest that the STAT3 pathway could be exploited as a drug target for ADPKD therapy.…”

“…4,7,8 Moreover, initial attempts to inhibit STAT3 in PKD mouse models have led to reduction of renal cyst growth. 7,8 These results suggest that the STAT3 pathway could be exploited as a drug target for ADPKD therapy. 9 STAT3 is known to be aberrantly activated in numerous forms of cancer, is a driving force of tumor cell proliferation, and is being pursued as a drug target for cancer therapy.…”

Scattered Deletion of PKD1 in Kidneys Causes a Cystic Snowball Effect and Recapitulates Polycystic Kidney Disease

“…Therefore, we performed immunohistochemistry to analyze phospho-STAT3 (pSTAT3), phospho-CREB, phospho-AKT, phospho-ERK1/2, and LCN2 expressions, which have been shown to be involved in PKD. 18,[23][24][25][26][27][28][29][30][31][32][33] The clustered distribution of cysts in an iKsp-Pkd1 del,lox mouse that was treated with low-dose tamoxifen, unilateral nephrectomy, and DCVC and euthanized 6 months after tamoxifen treatment (clustering is shown in Figure 6A), indeed, cooccurred with increased expression of these proteins specifically near cysts or clusters of cysts ( Figure 6B). We quantified the number of cysts/clusters that showed this effect in renal sections at two different locations in the kidneys of seven other mildly affected mice.…”