STAT signaling in polycystic kidney disease

Abstract

Mutations in the gene coding for the integral membrane protein polycystin-1 (PC1) are the cause of most cases of autosomal-dominant polycystic kidney disease (ADPKD), a very common disease that leads to kidney failure and currently lacks approved treatment. Recent work has revealed that PC1 can regulate the transcription factor STAT3, and that STAT3 is aberrantly activated in the kidneys of ADPKD patients and PKD mouse models. Recent approaches to directly inhibit STAT3 in PKD mouse models have been promising. Numerous signaling pathways are known to activate STAT3 and many have long been implicated in the pathogenesis of PKD-such as EGF/EGFR, HGF/c-Met, Src. However, a role of STAT3 in the pathogenesis of PKD had never been considered until now. Here, we review the current findings that suggest that STAT3 is a promising target for the treatment of PKD. Polycystic Kidney Disease ADPKD is a very common life-threatening, monogenic disease that is characterized by excessive proliferation and the growth of epithelial-lined cysts that eventually destroy the normal renal parenchyma [1, 2]. Most patients eventually progress to renal failure and will require dialysis or kidney transplantation. No approved treatment is currently available to halt or slow disease progression. However, a recent phase 3 trial using a vasopressin V 2receptor antagonist has shown promise in slowing the decline in kidney function [3]. ADPKD is caused by mutations in the PKD1 or PKD2 genes which encode the proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively. PC2 is a calcium channel of the TRP family, and forms a complex with PC1. In addition, PC1-which is mutated in most cases of ADPKD-has been shown to interact with a wide variety of signaling proteins and regulates numerous signaling pathways including heterotrimeric G proteins, wnt-, integrinand JAK/STAT-signaling, and the mTOR pathway. It has remained unclear which of these 1

The carboxy‐terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC‐activation

“…We found SRC and FCc in a common protein complex fitting to previous data linking FC to focal adhesion complexes 13 . Our data suggest that FCm can control the activation of SRC and may thus have a partly opposing function to the polycystin‐1 C‐term that activates SRC‐induced STAT3‐dependent transcription 5 …”

“…[9][10][11] First clinical trials on SRC inhibitors for PKD have been initiated (eg ClinicalTrials.gov identifiers NCT03096080 and NCT03203642). 12 SRC can be activated through multiple mechanisms, including increased intracellular cAMP concentration, 5 but details in PKD remain elusive.…”

Loss of Polycystin-1 causes cAMP-dependent switch from tubule to cyst formation

“…Upstream of ERBB, the cytoplasmic tyrosine kinase SRC mediates phosphorylation of EGFR in the catalytic domain which stabilizes kinase activation and promotes activation of RAF-kinases ( Biscardi et al., 1999 ; Parker et al., 2020 ). Furthermore, SRC enhances EGFR-dependent activation of the JAK-STAT pathway further promoting cyst growth ( Silva, 2004 ; Strubl et al., 2020 ). Interestingly, SRC has been shown to be activated by cAMP-induced protein kinase A ( Wang and Zhuang, 2017 ).…”

Is There a Functional Role of Mitochondrial Dysfunction in the Pathogenesis of ARPKD?

“…Importantly, the PCK rat, a preclinical model that phenotypically mimics ADPKD, genetically is orthologous to ARPKD. Overlapping dysregulation of signaling cascades has been described, e.g., with STAT3 activation in cyst-lining epithelial cells in both ARPKD and ADPKD (47)(48)(49). While the main gene affected in ARPKD has been known for two decades, the function of the PKHD1-encoded protein fibrocystin (FC) remains incompletely understood.…”