title: CaMKII as a pathological mediator of ER stress, oxidative stress, and mitochondrial dysfunction in a murine model of nephronophthisis.
abstract: Polycystic kidney diseases (PKDs) are genetic diseases characterized by renal cyst formation with increased cell proliferation, apoptosis, and transition to a secretory phenotype at the expense of terminal differentiation. Despite recent progress in understanding PKD pathogenesis and the emergence of potential therapies, the key molecular mechanisms promoting cystogenesis are not well understood. Here, we demonstrate that mechanisms including endoplasmic reticulum stress, oxidative damage, and compromised mitochondrial function all contribute to nephronophthisis-associated PKD. Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is emerging as a critical mediator of these cellular processes. Therefore, we reasoned that pharmacological targeting of CaMKII may translate into effective inhibition of PKD in jck mice. Our data demonstrate that CaMKII is activated within cystic kidney epithelia in jck mice. Blockade of CaMKII with a selective inhibitor results in effective inhibition of PKD in jck mice. Mechanistic experiments in vitro and in vivo demonstrated that CaMKII inhibition relieves endoplasmic reticulum stress and oxidative damage and improves mitochondrial integrity and membrane potential. Taken together, our data support CaMKII inhibition as a new and effective therapeutic avenue for the treatment of cystic diseases.
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Christina
authors.initials: C
authors.lastname: Bracken
authors.affiliation: Cardiovascular Research, Sanofi, Chilly-Mazarin, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Beauverger
authors.affiliation: Cardiovascular Research, Sanofi, Chilly-Mazarin, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Duclos
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Russo
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Rogers
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Hervé
authors.initials: H
authors.lastname: Husson
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Natoli
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ledbetter
authors.affiliation: Cardiovascular Research, Sanofi, Chilly-Mazarin, France.
authors.forename: Philip
authors.initials: P
authors.lastname: Janiak
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and.
authors.forename: Oxana
authors.initials: O
authors.lastname: Ibraghimov-Beskrovnaya
authors.affiliation: Rare Diseases, Sanofi-Genzyme R&D Center, Framingham, Massachusetts; and Nikolay.Bukanov@genzyme.com.
authors.forename: Nikolay O
authors.initials: NO
authors.lastname: Bukanov
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D007690:Polycystic Kidney Diseases / Q000378:metabolism*
chemical_list: D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: calcium/calmodulin-dependent protein kinase II; cystogenesis; endoplasmic reticulum; epithelial; nephronophthisis; oxidative stress; therapy