Genetic reduction of cilium length by targeting intraflagellar transport 88 protein impedes kidney and liver cyst formation in mouse models of autosomal polycystic kidney disease

Janani Ramesh, PhD
Department of Medicine
Division of Renal Medicine
Poster Overview

Primary cilia are linked to ADPKD. The detailed mechanisms of this linkage remain unclear. This study shows that primary cilium is elongated in kidneys from human patients with ADPKD and this elongation coincides with disease progression. Shortening cilia rescued the disease. Analysis of signaling pathways activated over disease progression identified a key inducer of cystogenesis downstream of cilia. Our data from human patients and mouse models advances the fundamental understanding of the genetic and biological mechanisms contributing to the

etiology and pathogenesis of polycystic kidney disease. Pharmaceutical modulation of cilium length and/or related signaling events might be new strategies to stop disease progression for ADPKD.

Scientific Abstract

Polycystin-1 (PC1) and -2 (PC2), products of the PKD1 and PKD2 genes, are mutated in autosomal dominant polycystic kidney disease (ADPKD). They localize to the primary cilia; however, their ciliary function is in dispute. Loss of either the primary cilia or PC1 or PC2 causes cyst formation. However, loss of both cilia and PC1 or PC2 inhibits cyst growth via an unknown pathway. To help define a pathway, we studied cilium length in human and mouse kidneys. We found   cilia   are   elongated   in    kidneys    from    patients    with    ADPKD    and    from    both Pkd1 and Pkd2knockout mice. Cilia elongate following polycystin inactivation. The role of intraflagellar transport proteins in Pkd1-deficient mice is also unknown. We found that inactivation of Ift88 (a gene expressing a core component of intraflagellar transport) in Pkd1 knockout mice, as well as in a new Pkd2 knockout mouse, shortened the elongated cilia, impeded kidney and liver cystogenesis, and reduced cell proliferation. Multi-stage in vivo analysis of signaling pathways revealed �-catenin activation as a prominent, early, and sustained event in disease onset and progression in Pkd2 single knockout but not in Pkd2.Ift88 double knockout mouse kidneys. Additionally, AMPK, mTOR and ERK pathways were altered in Pkd2single knockout mice but only AMPK and mTOR pathway alteration were rescued in Pkd2.Ift88 double knockout mice. Thus, our findings advocate an essential role of polycystins in the structure and function of the primary cilia and implicate �-catenin as a key inducer of cystogenesis downstream of the primary cilia. Our data suggest that modulating cilium length and/or its associated signaling events may offer novel therapeutic approaches for ADPKD.

Clinical Implications
This paper provides an evidence that regulating cilia length is a potential therapeutic for ADPKD patients. We found cilia length is elongated in human ADPKD tissue samples. We also found a similar elongation in two orthologous mouse models of ADPKD one modeling Pkd1 and another for Pkd2. In this paper we show that we successfully rescued cilia elongation by targeting Ift88 and by doing that we successfully rescued both kidney and liver cysts in both animal models. We also determined b-catenin activation at S675 (a PKA phosphorylation site) to be an early and sustained event driving cystogenesis. Our findings provide potential novel therapeutic targets and approaches that can translate to clinical trials. One approach is modulating cilium length by targeting IFT88 levels by siRNA technology or by using specific inhibitors before cyst formation in the kidney and liver. A second approach will be to target PKA or b-catenin by specific inhibitors targeted to the kidneys. In summary, the present study advances the field of ADPKD research and will lead to finding new targeted therapies in ADPKD with pitifully few available treatments. Furthermore, the study provides a blueprint for the design of other investigations of renal disease signaling in the continuing quest for targeted therapeutics in a field where few currently exist.
Research Areas
LinaShao, WassimEl-Jouni, Janani Ramesh, JingZhou
Principal Investigator
Jing Zhou, MD, PhD

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