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

• DOI: 10.15252/emmm.201404916
• Publication Date: 2015-02-03T07:19:41Z
• Authors: Christina Ising; Sybille Koehler; Sebastian Brähler; Carsten Merkwirth; Martin Höhne; Olivier R Baris; Henning Hagmann; Martin Kann; Francesca Fabretti; Claudia Dafinger; Wilhelm Bloch; Bernhard Schermer; Andreas Linkermann; Jens C Brüning; Christine E Kurschat; Roman‐Ulrich Müller; Rudolf J Wiesner; Thomas Langer; Thomas Benzing; Paul Thomas Brink...
• Keywords: insulin; Medicine (General); podocyte; [SDV]Life Sciences [q-bio]; QH426-470; Receptor, IGF Type 1; 03 medical and health sciences; R5-920; Prohibitins; Genetics; Animals; Insulin; Renal Insufficiency; Phosphorylation; Research Articles; Ribosomal Protein S6; 0303 health sciences; Receptor, Insulin; Mitochondria; 3. Good health; mitochondria; Mice, Inbred C57BL; Repressor Proteins; mTOR; Protein Processing, Post-Translational; Gene Deletion; Signal Transduction

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