Abstract
Transplantation of umbilical cord mesenchymal stem cells (UC-MSCs) is currently considered a novel therapeutic strategy for diabetic nephropathy (DN). However, the mechanisms by which UC-MSCs ameliorate renal fibrosis in DN are not well understood. Herein, we firstly investigated the therapeutic effects of mouse UC-MSC infusion on kidney structural and functional impairment in streptozotocin- (STZ-) induced diabetic mice. We found that the repeated injection with mUC-MSCs alleviates albuminuria, glomerulus injury, and fibrosis in DN mouse models. Next, mesangial cells were exposed to 5.6 mM glucose, 30 mM glucose, or mUC-MSC-conditioned medium, and then we performed western blotting, immunofluorescence, wound healing assay, and cell proliferation assay to measure extracellular matrix (ECM) proteins and matrix metalloproteinases (MMPs), myofibroblast transdifferentiation (MFT), and cell proliferation. We demonstrated that mUC-MSC paracrine decreased the deposition of fibronectin and collagen I by inhibiting TGF-β1-triggered MFT and cell proliferation mediated by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. Importantly, we provided evidence that the antifibrosis role of mUC-MSC paracrine in DN might be determined by exosomes shed by MSCs. Together, these findings reveal the mechanisms underlying the therapeutic effects of UC-MSCs on renal fibrosis in DN and provide the evidence for DN cell-free therapy based on UC-MSCs in the future.
Highlights
Diabetic nephropathy (DN), called diabetic glomerular sclerosis, is a serious microvascular complication caused by diabetic mellitus (DM) and is the leading reason for endstage renal disease (ESRD) [1, 2]
The inhibition of mUC-mesenchymal stem cells (MSCs) paracrine for mesangial cell proliferation and the levels of p-PI3K, p-Akt, p-ERK1/2, and p-P38 were reduced after administrated by MSC (GW4869)-conditioned medium (CM) (Figures 6(b) and 6(c)). These results indicated that exosomes play a key role in the antifibrosis effects of mUC-MSC paracrine in DN by inhibiting myofibroblast transdifferentiation (MFT) triggered by the TGF-β1/Smad2/3 signaling pathway and mesangial cell proliferation mediated by the PI3K/Akt and MAPK signaling pathways, and enhancing the expression of matrix metalloproteinases (MMPs)
The mechanisms by which mUC-MSC paracrine attenuates renal fibrosis involve the inhibition of MFT triggered by the TGF-β1/Smad2/3 signaling pathway and mesangial cell proliferation mediated by the PI3K/Akt and MAPK signal transduction pathways, and elevating MMP levels
Summary
Diabetic nephropathy (DN), called diabetic glomerular sclerosis, is a serious microvascular complication caused by diabetic mellitus (DM) and is the leading reason for endstage renal disease (ESRD) [1, 2]. An animal study has shown that human UC-MSCs (hUC-MSCs) improved glomerular hypertrophy, basement membrane thickening, and urinary protein and creatinine clearance in DN rats [19]. We demonstrate that repeated administration of mUC-MSCs attenuates the progression of DN by improving glomerular hypertrophy, base membrane thickening, podocyte process effacement, and fibrotic abnormality in STZinduced diabetic mice. MUC-MSC paracrine can alleviate renal fibrosis in the DN cell model via inhibition of MFT caused by TGF-β1, blocking mesangial cell proliferation induced by PI3K/Akt and MAPK signaling pathways, and elevating the levels of MMP2 and MMP9. It is worth noting that we are the first to provide the proof that the antifibrotic effect of mUC-MSC paracrine might be mainly due to exosomes, which adds to our understanding of the role of UC-MSC paracrine in alleviating renal fibrosis in DN and provides the evidence for the future cell-free therapeutic strategy based on UC-MSCs for DN
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