Inhibition of insulin/IGF‐1 receptor signaling protects from mitochondria‐mediated kidney failure

EMBO Molecular Medicine

Christina Ising²  Sybille Koehler²  Sebastian Brähler²  Carsten Merkwirth⁴  Martin Höhne²  Olivier R Baris⁵  Henning Hagmann²  Martin Kann²  Francesca Fabretti²  Claudia Dafinger²  Wilhelm Bloch³  Bernhard Schermer²  Andreas Linkermann¹  Jens C Brüning⁶  Christine E Kurschat²  Roman-Ulrich Müller²  Rudolf J Wiesner⁵  Thomas Langer⁴  Thomas Benzing² 

[1] Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel, Germany;Department II of Internal Medicine and Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany;Department of Molecular and Cellular Sport Medicine, Institute of Cardiovascular Research and Sport Medicine, German Sport University Cologne, Cologne, Germany;Institute for Genetics, University of Cologne, Cologne, Germany;Center for Physiology and Pathophysiology, Institute for Vegetative Physiology, University of Cologne, Cologne, Germany;Cologne Cluster of Excellence on Cellular Stress Responses in Ageing-Associated Diseases (CECAD) and Systems Biology of Ageing Cologne (Sybacol), University of Cologne, Cologne, Germany

关键词: insulin;    mitochondria;    mTOR;    podocyte;   

DOI  :  10.15252/emmm.201404916

来源: Wiley

【 摘 要 】

Abstract

Mitochondrial dysfunction and alterations in energy metabolism have been implicated in a variety of human diseases. Mitochondrial fusion is essential for maintenance of mitochondrial function and requires the prohibitin ring complex subunit prohibitin-2 (PHB2) at the mitochondrial inner membrane. Here, we provide a link between PHB2 deficiency and hyperactive insulin/IGF-1 signaling. Deletion of PHB2 in podocytes of mice, terminally differentiated cells at the kidney filtration barrier, caused progressive proteinuria, kidney failure, and death of the animals and resulted in hyperphosphorylation of S6 ribosomal protein (S6RP), a known mediator of the mTOR signaling pathway. Inhibition of the insulin/IGF-1 signaling system through genetic deletion of the insulin receptor alone or in combination with the IGF-1 receptor or treatment with rapamycin prevented hyperphosphorylation of S6RP without affecting the mitochondrial structural defect, alleviated renal disease, and delayed the onset of kidney failure in PHB2-deficient animals. Evidently, perturbation of insulin/IGF-1 receptor signaling contributes to tissue damage in mitochondrial disease, which may allow therapeutic intervention against a wide spectrum of diseases.

Synopsis

Podocyte-specific PHB2 loss results in severe kidney disease that is alleviated by insulin and IGF-1 receptors deletion or rapamycin treatment, demonstrating not only a causal link between mitochondrial dysfunction and kidney disease but also putative therapeutic avenues.

• Deletion of the mitochondrial protein PHB2 in glomerular podocytes caused progressive proteinuria and death of the animals due to end-stage kidney failure.
• Contrary to generally held beliefs loss of PHB2 did not cause overt defects in mitochondrial respiratory activity or increased production of ROS but was accompanied by hyperactive insulin/IGF-1 receptor signaling.
• Inhibition of the insulin/IGF-1 signaling system through genetic deletion of insulin receptor alone or in combination with the IGF-1 receptor or treatment with mTOR inhibitor rapamycin, alleviated renal disease and delayed the onset of kidney failure in PHB2-deficient animals.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.