Canonical Wnt inhibitors ameliorate cystogenesis in a mouse ortholog of human ADPKD

The Role of Wnt Signalling in Chronic Kidney Disease (CKD)

“…In a study where Pkd2 was knocked out from a renal collecting duct cell line, there was evidence of ciliogenesis defects, together with increased β-catenin and AXIN-2 and c-Myc expression [55,111,112]. Further supporting this, is evidence from a Pkd2 KO mouse line where the mutant mouse presented with kidney cysts, whilst the kidney tissue also demonstrated elevated levels of active, nuclear and total β-catenin (Ctnnb1) proteins alongside Axin-2, c-Myc and cyclin D1 proteins [108]. In the same study, loss of one Ctnnb1 allele rescued the renal cystic phenotype and reduced the increased levels of Wnt target genes Axin-2, c-Myc and cyclin D1 [108].…”

“…Further supporting this, is evidence from a Pkd2 KO mouse line where the mutant mouse presented with kidney cysts, whilst the kidney tissue also demonstrated elevated levels of active, nuclear and total β-catenin (Ctnnb1) proteins alongside Axin-2, c-Myc and cyclin D1 proteins [108]. In the same study, loss of one Ctnnb1 allele rescued the renal cystic phenotype and reduced the increased levels of Wnt target genes Axin-2, c-Myc and cyclin D1 [108]. In another study, the conditional inactivation of APC, a tumour suppressor that forms a key part of the multiprotein β-catenin destruction complex in the canonical Wnt signalling pathway resulted in cystic renal neoplasia [109].…”

“…The group's data shows that RAS genes are upregulated by β-catenin in vitro and in vivo and that the upregulation can be blocked by β-catenin inhibitors, such as ICG-001 [91,107]. Other evidence has found that canonical Wnt signalling inhibition via XAV939, a tankyrase inhibitor that promotes β-catenin degradation and LGK974, a Porcupine inhibitor that blocks lipid modification of Wnt proteins, delays the progression of renal cystogenesis and reduces elevated levels of β-catenin and of Wnt target genes, Axin-2, c-Myc and cyclin D1 in mutant mice [108].…”

Aquatic models of human ciliary diseases

“…As β‐catenin is required for canonical Wnt signaling, degradation of β‐catenin should lead to decreased Wnt signaling. Other theories involve calcium signaling, given that calcium ions can also inhibit Wnt signaling via the Wnt/Ca 2+ pathway and the cilia contain mechanoresponsive calcium channels called polycystins (Kühl, Sheldahl, Malbon, & Moon, 2000; Li et al, 2018). Alternatively, it is also possible that the polycystin complex more directly targets Wnt signaling through direct binding of β‐catenin (Lal et al, 2008).…”

Combination of curcumin and ginkgolide B inhibits cystogenesis by regulating multiple signaling pathways

“…Small-molecule CFTR inhibitors decrease cyst fluid secretion in PKD by inhibiting the function of CFTR, which in turn stimulates chloride secretion, and thus cystic fluid secretion ( 12 ). Other treatments that decrease cyst growth in ADPKD include tolvaptan ( 18 , 19 ), src inhibitors ( 20 ), Wnt inhibitors ( 21 ), mTOR inhibitors ( 22 ), pioglitazone ( 23 , 24 ), triptolide ( 25 ), Ganoderma triterpenes ( 26 ) and Quercetin ( 27 ). Tolvaptan has been approved for the treatment of ADPKD in Europe and other countries throughout the world ( 28 ).…”