RT Journal Article
SR Electronic
T1 Intraflagellar transport-A deficiency attenuates ADPKD in a renal tubular- and maturation-dependent manner
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.26.061796
DO 10.1101/2020.04.26.061796
A1 Wei Wang
A1 Luciane M. Silva
A1 Henry H. Wang
A1 Matthew A. Kavanaugh
A1 Tana S. Pottorf
A1 Bailey A. Allard
A1 Damon T. Jacobs
A1 Rouchen Dong
A1 Joseph T. Cornelius
A1 Aakriti Chaturvedi
A1 Michele T. Pritchard
A1 Madhulika Sharma
A1 Chad Slawson
A1 Darren P. Wallace
A1 James P. Calvet
A1 Pamela V. Tran
YR 2020
UL http://biorxiv.org/content/early/2020/10/21/2020.04.26.061796.abstract
AB 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 potential therapeutic value. To broaden the role of ciliary dysfunction, here we investigate the role of global deletion of Ift-A gene, Thm1, in juvenile and adult ADPKD mouse models. In cyst-lining cells of both juvenile and adult ADPKD models, cortical collecting duct cilia lengths and cytoplasmic and nuclear levels of the nutrient sensor, O-linked β-Nacetylglucosamine (O-GlcNAc) were increased. Relative to juvenile Pkd2 conditional knock-out mice, deletion of Thm1 together with Pkd2 both increased and reduced cystogenesis in a tubule-specific manner without altering kidney function, inflammation, cilia lengths, and ERK, STAT3 and OGlcNAc signaling. In contrast, Thm1 deletion in adult ADPKD mouse models markedly attenuated almost all features of PKD, including renal cystogenesis, inflammation, cilia lengths, and ERK, STAT3 and O-GlcNAc signaling. These data suggest that differential factors in the microenvironments between renal tubules and between developing and mature kidneys influence cilia and ADPKD pathobiology. Further, since O-GlcNAcylation directly regulates ciliary homeostasis and the balance between glycolysis and oxidative phosphorylation, we propose that increased O-GlcNAcylation may promote certain key ADPKD pathological processes.Competing Interest StatementThe authors have declared no competing interest.