Federica Barutta1, Shunsuke Kimura2, Koji Hase2, Stefania Bellini3, Beatrice Corbetta3, Alessandro Corbelli4, Fabio Fiordaliso4, Antonella Barreca5, Mauro Giulio Papotti6, Gian Marco Ghiggeri7, Gennaro Salvidio8, Dario Roccatello9,10, Valentina Audrito3, Silvia Deaglio3, Roberto Gambino3, Stefania Bruno3, Giovanni Camussi3, Miriam Martini11, Emilio Hirsch11, Marilena Durazzo3, Hiroshi Ohno12, Gabriella Gruden3. 1. Department of Medical Sciences, University of Turin, Turin, Italy federica.barutta@unito.it. 2. Division of Biochemistry, Faculty of Pharmacy, Keio University, Tokyo, Japan. 3. Department of Medical Sciences, University of Turin, Turin, Italy. 4. Department of Cardiovascular Medicine, Institute of Pharmacological Research Mario Negri, Scientific Institute for Hospitalization and Care (IRCCS), Milan, Italy. 5. Division of Pathology, Molinette Hospital, Turin, Italy. 6. Department of Oncology, University of Turin, Turin, Italy. 7. Division of Nephrology, Dialysis, Transplantation, Gaslini Children's Hospital, Genoa, Italy. 8. Scientific Institute for Hospitalization and Care (IRCCS), San Martino University Hospital Clinic, Genoa, Italy. 9. Center of Research of Immunopathology and Rare Diseases, Coordinating Center of Piemonte and Valle d'Aosta Network for Rare Diseases, S. Giovanni Bosco Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. 10. Nephrology and Dialysis, Department of Clinical and Biological Sciences, S. Giovanni Bosco Hospital, University of Turin, Turin, Italy. 11. Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy. 12. Laboratory for Intestinal Ecosystem, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan.
Abstract
BACKGROUND: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. METHODS: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). RESULTS: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. CONCLUSIONS: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.
BACKGROUND: Podocyte dysfunction and loss are major determinants in the development of proteinuria. FSGS is one of the most common causes of proteinuria, but the mechanisms leading to podocyte injury or conferring protection against FSGS remain poorly understood. The cytosolic protein M-Sec has been involved in the formation of tunneling nanotubes (TNTs), membrane channels that transiently connect cells and allow intercellular organelle transfer. Whether podocytes express M-Sec is unknown and the potential relevance of the M-Sec-TNT system in FSGS has not been explored. METHODS: We studied the role of the M-Sec-TNT system in cultured podocytes exposed to Adriamycin and in BALB/c M-Sec knockout mice. We also assessed M-Sec expression in both kidney biopsies from patients with FSGS and in experimental FSGS (Adriamycin-induced nephropathy). RESULTS: Podocytes can form TNTs in a M-Sec-dependent manner. Consistent with the notion that the M-Sec-TNT system is cytoprotective, podocytes overexpressed M-Sec in both human and experimental FSGS. Moreover, M-Sec deletion resulted in podocyte injury, with mitochondrial abnormalities and development of progressive FSGS. In vitro, M-Sec deletion abolished TNT-mediated mitochondria transfer between podocytes and altered mitochondrial bioenergetics. Re-expression of M-Sec reestablishes TNT formation and mitochondria exchange, rescued mitochondrial function, and partially reverted podocyte injury. CONCLUSIONS: These findings indicate that the M-Sec-TNT system plays an important protective role in the glomeruli by rescuing podocytes via mitochondrial horizontal transfer. M-Sec may represent a promising therapeutic target in FSGS, and evidence that podocytes can be rescued via TNT-mediated horizontal transfer may open new avenues of research.
Authors: Ilaria Ottonelli; Riccardo Caraffi; Giovanni Tosi; Maria Angela Vandelli; Jason Thomas Duskey; Barbara Ruozi Journal: Int J Mol Sci Date: 2022-02-17 Impact factor: 5.923