CaMKII as a pathological mediator of ER stress, oxidative stress, and mitochondrial dysfunction in a murine model of nephronophthisis
| Autor: | Olivier Duclos, Christina Bracken, Ryan J. Russo, Kelly A. Rogers, Philip Janiak, Steven R. Ledbetter, Thomas A. Natoli, Nikolay O. Bukanov, Oxana Ibraghimov-Beskrovnaya, Philippe Beauverger, Hervé Husson |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Physiology 030204 cardiovascular system & hematology Mitochondrion Biology Kidney medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Mediator Ca2+/calmodulin-dependent protein kinase medicine Polycystic kidney disease Animals Cystic kidney Polycystic Kidney Diseases Endoplasmic reticulum Endoplasmic Reticulum Stress musculoskeletal system medicine.disease Mitochondria Cell biology Oxidative Stress 030104 developmental biology cardiovascular system Unfolded protein response Calcium-Calmodulin-Dependent Protein Kinase Type 2 Oxidative stress |
| Zdroj: | American Journal of Physiology-Renal Physiology. 310:F1414-F1422 |
| ISSN: | 1522-1466 1931-857X |
| Popis: | 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. Ca2+/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. |
| Databáze: | OpenAIRE |
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