Abstract
The underlying therapeutic mechanism of renal tubular epithelium repair of diabetic nephropathy (DN) by bone marrow-derived mesenchymal stem cells (BM-MSCs) has not been fully elucidated. Recently, mitochondria (Mt) transfer was reported as a novel action of BM-MSCs to rescue injured cells. We investigated Mt transfer from systemically administered BM-MSCs to renal proximal tubular epithelial cells (PTECs) in streptozotocin (STZ)-induced diabetic animals. BM-MSCs also transferred their Mt to impaired PTECs when co-cultured in vitro, which suppressed apoptosis of impaired PTECs. Additionally, BM-MSC-derived isolated Mt enhanced the expression of mitochondrial superoxide dismutase 2 and Bcl-2 expression and inhibited reactive oxygen species (ROS) production in vitro. Isolated Mt also inhibited nuclear translocation of PGC-1α and restored the expression of megalin and SGLT2 under high glucose condition (HG) in PTECs. Moreover, isolated Mt directly injected under the renal capsule of STZ rats improved the cellular morphology of STZ-PTECs, and the structure of the tubular basement membrane and brush border in vivo. This study is the first to show Mt transfer from systemically administered BM-MSCs to damaged PTECs in vivo, and the first to investigate mechanisms underlying the potential therapeutic effects of Mt transfer from BM-MSCs in DN.
Highlights
Mitochondria (Mt) transfer has been proposed as a novel action of mesenchymal stem cells (MSCs)
We investigated the additional effect of bone marrow-derived mesenchymal stem cells (BM-MSCs)-Mt using NRK-52E cells under both high glucose (HG) and low glucose (LG) conditions to examine the effect of BM-MSC-Mt on intracellular pathways of mitochondrial proteins associated with renal protection
Incorporated Mt acted on the endogenous Mt fraction of proximal tubular epithelial cells (PTECs) to suppress apoptosis by regulating Mt-related factors, such as Bcl-2, Bax and PGC-1α and inhibiting reactive oxygen species (ROS) production, resulting in the recovery of the expression of transporters, such as megalin and SGLT2, and structural restoration of renal tubules
Summary
Mitochondria (Mt) transfer has been proposed as a novel action of mesenchymal stem cells (MSCs). The neuroprotective effects of Mt transfer were revealed in cortical neurons after stroke[4] These studies concluded that Mt transfer from MSCs increased activity of the respiratory chain complex and ATP levels in damaged cells in vivo and in vitro. In this study, we first present the phenomenon of Mt transfer in vivo and in vitro, and investigated its crucial roles for the repair of damaged PTECs in the kidney of a DN model as follows: (1) anti-apoptotic and anti-degenerative effects for PTECs; (2) inhibition of ROS production by regulating mitochondria-related factors, e.g., SOD2, Bcl-2, Bax and PGC-1α; (3) recovery of the expression of functional transporters in PTECs, e.g., Megalin and SGLT2; and (4) structural improvement of PTECs and reorganisation of tubular epithelium.
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