Ankhd1enhances polycystic kidney disease development via promoting proliferation and fibrosis

Abstract

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common genetic kidney disorder resulting in 10% of patients with renal failure. The molecular events responsible for the relentless growth of cysts are not defined. Thus, identification of novel drivers of ADPKD may lead to new therapies. Ankyrin Repeat and Single KH domain-1 (ANKHD1) controls cancer cell proliferation, yet its role in ADPKD is unexplored. Here, we present the first data that identify ANKHD1 as a driver of proliferative growth in cellular and mouse models of ADPKD. Using the first Ankhd1-deficient mice, we demonstrate that Ankhd1 heterozygosity potently reduces cystic growth and fibrosis, in a genetically orthologous mouse model of ADPKD. We performed transcriptome-wide profiling of patient-derived ADPKD cells with and without ANKHD1 siRNA silencing, revealing a major role for ANKHD1 in the control of cell proliferation and matrix remodelling. We validated the role of ANKHD1 in enhancing proliferation in patient-derived cells. Mechanistically ANKHD1 promotes STAT5 signalling in ADPKD mice. Hence, ANKHD1 is a novel driver of ADPKD, and its inhibition may be of therapeutic benefit.

Emerging functions for ANKHD1 in cancer-related signaling pathways and cellular processes

“…In drosophila, mask is the only protein form, but in humans, there are two orthologous proteins. Despite recent data, indi-cating ANKHD1 or ANKRD17 acted similarly in the nuclear translocation of YAP1 (12), results from knockout mice suggest additional non-redundant roles for ANKHD1 and ANKRD17, since the knockout of one of the proteins results in developmental failure and embryo lethality (18,35). More in-depth studies on the impact of ANKHD1 knockout in murine models are still needed.…”

“…Furthermore, ANKHD1 silencing reduced STAT3 activation, which is an indicative of JAK/STAT pathway activity (17). In a murine model of autosomal dominant polycystic kidney disease, ANKHD1 increases STAT5 phosphorylation, induces cell proliferation, and contributes to the development and progression of the disease (18). In 2013, it was described that mask acts as a yorkie (yki) cofactor, regulating the activity of the Hippo signaling pathway (19,20).…”