Protective Role of the M-Sec–Tunneling Nanotube System in Podocytes

Abstract

BackgroundPodocyte 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.MethodsWe 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).ResultsPodocytes 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.ConclusionsThese 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.

Protective effect of the tunneling nanotube-TNFAIP2/M-sec system on podocyte autophagy in diabetic nephropathy

“…Podocyte overexpression of TNFAIP2 also occurs in FSGS [ 54 ], raising the hypothesis that TNFAIP2 induction may be a common response to podocyte injury. TNFAIP2 upregulation is likely a compensatory mechanism aimed to limit glomerular injury.…”

“…There is little information on the TNFAIP2-TNT system in the kidney. However, podocytes can express TNFAIP2 and their exposure to either serum deprivation or adriamycin induces a TNFAIP2-TNT-dependent transfer of mitochondria from healthy to injured podocytes [ 54 ]. In addition, in vivo deletion of Tnfaip2 causes the spontaneous development of focal segmental glomerulosclerosis (FSGS) in the susceptible BALB/c mouse strain [ 54 ].…”

Mechanisms of podocyte injury and implications for diabetic nephropathy

“…In adriamycin-treated podocytes the M-Sec–TNT system allows mitochondria transfer, ameliorates mitochondrial bioenergetics, and partially reverts podocyte injury. Moreover, in vivo M-Sec is overexpressed by podocytes in both human and experimental FSGS and M-Sec deletion causes podocyte injury, mitochondrial abnormalities, and the spontaneous development of progressive FSGS [ 322 ].…”

Tunneling Nanotubes: A New Target for Nanomedicine?

“…Another widely used technique to induce the formation of TNTs in vitro is also to transfect cells with proteins involved in cytoskeletal mobility and cell adhesion. The administration of mSEC [66,67], which triggers the formation of TNTs due to the higher dynamicity of the cytoskeleton, is a primary example. Most drugs used and tested in cell cultures have been also linked to an increase in the connections between cells due to their stressful effect, especially considering anticancer drugs and antibiotics [68][69][70].…”