Genetic and Pharmacological Investigations into a Zebrafish Model of ADPKD

Abstract

This research aimed to identify molecular mechanisms underlying autosomal dominant polycystic kidney disease (ADPKD) using genetic and pharmacological approaches in a zebrafish model of ADPKD. Specifically, our goal was to determine if histone deacetylase (HDAC) or Activin receptor-like kinase 5 (ALK5) inhibition would be able to reduce the tail curvature phenotype in a zebrafish model of ADPKD. Polycystic kidney disease (PKD) is a condition in which the kidneys develop multiple fluid-filled cysts. It is one of the most common hereditary kidney disorders, in which nearly half of all afflicted patients end up in end-stage renal failure, and the disease as a whole account for about 10% of all end-stage renal disease cases worldwide (National Institute of Diabetes and Digestive and Kidney Diseases, 2019). The cause of ADPKD in humans is due to mutations in one of the two genes, PKD1 and PKD2 that encode polycystin-1 (PC1) and polycystin-2 (PC2), respectively. Several target mechanisms acting downstream of PC1 and PC2, including cAMP overload, aberrant Ca2+ signaling, planar cell polarity, HDAC activation, and fibrosis, have been proposed to underlie ADPKD development and progression. Despite the extensive research and well-known genetic cause of ADPKD, there is only one approved therapy at this time. Tolvaptan is a selective arginine vasopressin (AVP) V2-receptor antagonist that delays the increase in kidney volume, slows the decline in renal function, and reduces pain levels for patients suffering from ADPKD. Despite the benefits of this drug, end-stage renal disease (ESRD) is delayed by just over five years, on average, and side effects include increased thirst and polyuria, along with hepatotoxicity (Khan, Rawala, Siddiqui, Abid, & Aslam, 2019; Sans-Atxer & Joly, 2018). The limited benefit of Tolvaptan, coinciding with harmful side effects, indicates a need for more effective, longer-lasting, and safer treatments. To identify specific target mechanisms underlying ADPKD progression in vivo, we developed a robust zebrafish model of ADPKD. Loss of pkd2 in zebrafish results in a characteristic tail curvature, offering a visual phenotype for genetic and pharmacological screening. We selected candidate genes and pathways implicated in the development and progression of ADPKD pathology and used small molecules to modulate the activity of these candidates. Here we report that selective inhibition of specific classes of HDACs does not rescue tail curvature phenotype caused by the loss of pkd2. Importantly, we show that multiple, selective ALK5 inhibitors rescue the tail curvature phenotype. This work indicates that the Activin pathway is a promising target for further research as a potential therapy for ADPKD.