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Abstract: TH-OR69

Ablation of Long Noncoding RNA Hoxb3os Exacerbates Cystogenesis in Mouse Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Aboudehen, Karam S., Stony Brook University, Stony Brook, New York, United States
  • Weisser, Ivan D., Regents of the University of Minnesota, Minneapolis, Minnesota, United States
  • Eckberg, Kara, Regents of the University of Minnesota, Minneapolis, Minnesota, United States
  • D'Amico, Stephen, Stony Brook University, Stony Brook, New York, United States
  • Buttram, Daniel Joseph, Regents of the University of Minnesota, Minneapolis, Minnesota, United States
Background

Autosomal dominant polycystic kidney disease (ADPKD) is a monogenic disorder characterized by the formation of cysts in the kidney, and is primarily caused by mutations in two genes, PKD1 and PKD2. Long non-coding RNA (lncRNA) are >200 bp in length, lack an open reading frame, and have recently emerged as epigenetic regulators of development and disease. The involvement of lncRNAs in ADPKD is not known.

Methods

In this study, we investigated the role of lncRNA Hoxb3os in ADPKD by ablating its expression in the mouse.

Results

Phenotypic analysis revealed that Hoxb3os-null mice were viable and had grossly normal kidney morphology. At the molecular level, Hoxb3os-null kidneys showed activation of mTOR/AKT signaling and subsequent increase in cell proliferation. To determine whether downregulation of Hoxb3os affects cystogenesis, we crossed the Hoxb3os-null mouse to two orthologues Pkd1 mouse models: Pkhd1/Cre;Pkd1F/F (rapid cyst progression) and Pkd1RC/RC (slow cyst progression). Ablation of Hoxb3os exacerbated cyst growth in both mouse models. To gain insight into the mechanism(s) whereby Hoxb3os inhibition promotes cystogenesis, we performed proteomic analysis of mTOR/AKT pathway between single knockout (Pkd1-/-, SKO) and double knockout (Pkd1-/- and Hoxb3os-/-, DKO) mice. Compared to SKO, DKO mice displayed increased levels of total and phosphorylated RICTOR, a protein component specific to mTORC2. This was accompanied by enhanced phosphorylation of AKT at Ser473, a known mTORC2 phosphorylation site. Physiologically, kidneys from DKO mice displayed between 40-50% increase in cell proliferation.

Conclusion

Results from this study indicate that ablation of Hoxb3os in mouse ADPKD dysregulated mTORC2 and exacerbated cystogenesis.

Funding

  • NIDDK Support