TY - JOUR
T1 - Protective role of the M-sec-tunneling nanotube system in podocytes
AU - Barutta, Federica
AU - Kimura, Shunsuke
AU - Hase, Koji
AU - Bellini, Stefania
AU - Corbetta, Beatrice
AU - Corbelli, Alessandro
AU - Fiordaliso, Fabio
AU - Barreca, Antonella
AU - Papotti, Mauro Giulio
AU - Ghiggeri, Gian Marco
AU - Salvidio, Gennaro
AU - Roccatello, Dario
AU - Audrito, Valentina
AU - Deaglio, Silvia
AU - Gambino, Roberto
AU - Bruno, Stefania
AU - Camussi, Giovanni
AU - Martini, Miriam
AU - Hirsch, Emilio
AU - Durazzo, Marilena
AU - Ohno, Hiroshi
AU - Gruden, Gabriella
N1 - Publisher Copyright:
© 2021 by the American Society of Nephrology
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105833604&partnerID=8YFLogxK
U2 - 10.1681/ASN.2020071076
DO - 10.1681/ASN.2020071076
M3 - Article
SN - 1046-6673
VL - 32
SP - 1114
EP - 1130
JO - Journal of the American Society of Nephrology : JASN
JF - Journal of the American Society of Nephrology : JASN
IS - 5
ER -