Department of Pharmacology, University of Washington, Seattle, United States
Mitchell H Omar
Department of Pharmacology, University of Washington, Seattle, United States
Ankita Roy
Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States
Nelly M Cruz
Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States
Jerome Falcone
Department of Pharmacology, University of Washington, Seattle, United States
Kiana N Jones
Department of Pharmacology, University of Washington, Seattle, United States
Department of Pharmacology, University of Washington, Seattle, United States
Jonathan Himmelfarb
Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States
Benjamin S Freedman
Kidney Research Institute, Division of Nephrology, Department of Laboratory Medicine and Pathology, University of Washington, Seattle, United States; Institute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, United States
Pathophysiological defects in water homeostasis can lead to renal failure. Likewise, common genetic disorders associated with abnormal cytoskeletal dynamics in the kidney collecting ducts and perturbed calcium and cAMP signaling in the ciliary compartment contribute to chronic kidney failure. We show that collecting ducts in mice lacking the A-Kinase anchoring protein AKAP220 exhibit enhanced development of primary cilia. Mechanistic studies reveal that AKAP220-associated protein phosphatase 1 (PP1) mediates this phenotype by promoting changes in the stability of histone deacetylase 6 (HDAC6) with concomitant defects in actin dynamics. This proceeds through a previously unrecognized adaptor function for PP1 as all ciliogenesis and cytoskeletal phenotypes are recapitulated in mIMCD3 knock-in cells expressing a phosphatase-targeting defective AKAP220-ΔPP1 mutant. Pharmacological blocking of local HDAC6 activity alters cilia development and reduces cystogenesis in kidney-on-chip and organoid models. These findings identify the AKAP220-PPI-HDAC6 pathway as a key effector in primary cilia development.