Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner

Abstract

Background: Primary cilia are sensory organelles that are built and maintained by intraflagellar transport (IFT) multi-protein complexes. Deletion of certain ciliary genes in Autosomal Dominant Polycystic Kidney Disease (ADPKD) mouse models markedly attenuates PKD severity, indicating that a component of cilia dysfunction may have critical therapeutic potential. Method:We have ablated the Ift-A gene, Thm1, globally in juvenile and adult mouse models of ADPKD.Results: Relative to juvenile Pkd2 conditional knock-out mice, deletion of Thm1 together with Pkd2 resulted in a complex phenotype, with reduced kidney weight/body weight (KW/BW) ratios, reduced cortical collecting duct-derived cysts, but increased proximal tubular and glomerular dilations, and similar blood urea nitrogen (BUN) levels. Additionally, primary cilia of cortical collecting duct epithelia were lengthened in Pkd2 conditional knock-out kidneys, as well as in Pkd2;Thm1 double knock-out kidneys. In contrast, Thm1 deletion in adult ADPKD mouse models markedly reduced multiple disease parameters, including KW/BW ratios, collecting duct-and loop of Henle-derived cysts, proximal tubular dilations, and BUN levels. Further, primary cilia lengths of cortical collecting duct epithelia were increased in Pkd1 and Pkd2 conditional knock-out mice, but similar to control in Pkd1;Thm1 and Pkd2;Thm1 double knock-out mice.Conclusions: These data reveal that during kidney development, Thm1 both promotes and inhibits different aspects of ADPKD renal cystogenesis in a tubule-dependent manner; however, during adult kidney homeostasis, Thm1 promotes virtually all features of ADPKD renal cyst growth. These findings suggest that differential factors between tubules and between developing versus mature renal microenvironments influence cilia dysfunction and ADPKD pathobiology.

Interactions between TULP3 tubby domain cargo site and ARL13B amphipathic helix promote lipidated protein transport to cilia

“…In line with a role of TULP3 in trafficking multiple cargoes, TULP3 and IFT-A have been implicated in neural tube patterning (Legue and Liem, 2020;Liem et al, 2012;Mukhopadhyay et al, 2013;Norman et al, 2009;Qin et al, 2011), renal cystogenesis (Hwang et al, 2019;Legue and Liem, 2019;Wang et al, 2020) and adipogenesis (Hilgendorf et al, 2019;Wu et al, 2020).…”

IFT-A deficiency in juvenile mice impairs biliary development and exacerbates ADPKD liver disease

“…Yet in the kidney, perinatal deletion of Thm1 causes cysts 20 , and deletion of Thm1 in juvenile Pkd2 cko mice affects cystogenesis in a tubular-dependent manner. Further, deletion of Thm1 in adult Pkd2 cko mice attenuates renal cystogenesis 42 . Thus, Thm1 influences cystogenesis in the kidney but not in the liver.…”