In:
Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 5 ( 2021-5), p. 1114-1130
Abstract:
FSGS is an important cause of end-stage renal failure, 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. The authors found that the cytosolic protein M-Sec, which is involved in the development of TNTs, is induced in FSGS and allows replacement of dysfunctional podocyte organelles via TNTs, whereas M-Sec abrogation leads to FSGS onset. These findings reveal the M-Sec–TNT system plays an important protective role in podocytes and may represent a novel therapeutic target in FSGS. Demonstration that dysfunctional podocyte mitochondria can be replaced through horizontal TNT-mediated transfer may set the stage for strategies of regenerative cell-based therapy. 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.
Type of Medium:
Online Resource
ISSN:
1046-6673
,
1533-3450
DOI:
10.1681/ASN.2020071076
Language:
English
Publisher:
Ovid Technologies (Wolters Kluwer Health)
Publication Date:
2021
detail.hit.zdb_id:
2029124-3
