Abstract
Acute kidney injury (AKI) predisposes patients to an increased risk into progressive chronic kidney disease (CKD), however effective treatments are still elusive. This study aimed to investigate the therapeutic efficacy of human adipose-derived MSCs (hAD-MSCs) in the prevention of AKI-CKD transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process. C57BL/6 mice were subjected to unilateral renal ischemia/reperfusion (I/R) with or without hAD-MSC treatment. We found that hAD-MSC treatment upregulated the expression of tubular Sox9, promoted tubular regeneration, attenuated AKI, and mitigated subsequent renal fibrosis. However, these beneficial effects were abolished by a drug inhibiting the release of exosomes from hAD-MSCs. Similarly, Sox9 inhibitors reversed these protective effects. Further, we verified that hAD-MSCs activated tubular Sox9 and prevented TGF-β1-induced transformation of TECs into pro-fibrotic phenotype through exosome shuttling in vitro, but the cells did not inhibit TGF-β1-induced transition of fibroblasts into myofibroblasts. Inhibiting the release of exosomes from hAD-MSCs or the expression of Sox9 in TECs reversed these antifibrotic effects. In conclusion, hAD-MSCs employed exosomes to mitigate AKI-CKD transition through tubular epithelial cell dependent activation of Sox9.
Highlights
Acute kidney injury (AKI) is an increasingly clinical problem associated with high morbidity and mortality, especially among intensive care unit patients (>50%) [1,2,3]
This study aimed to investigate the therapeutic efficacy of human adiposederived MSCs in the prevention of AKI-chronic kidney disease (CKD) transition, and illuminate the role of Sox9, a vital transcription factor in the development of kidney, in this process
We report here the finding that hAD-MSCs employed exosomes to attenuate murine AKI to CKD progression through tubular epithelial cell dependent Sox9 activation in model of unilateral renal I/R injury
Summary
AKI is an increasingly clinical problem associated with high morbidity and mortality, especially among intensive care unit patients (>50%) [1,2,3]. Despite the fact that some AKI patients returned to normal renal function after supportive treatments, it shows a 25 percent increase in the risk of dormant progression to www.impactjournals.com/oncotarget. The pathophysiology of AKI is characterized as renal tubular epithelial cell damage, inflammatory infiltration and vascular dysfunction, which initiates the self-repair mechanism of the kidney [7, 8]. Maladaptive repair presents as the persistent proliferation, activation of myofibroblasts and excellular matrix deposited in the renal interstitium [11, 12], which are the hallmarks of AKI to CKD transition. The underlying mechanisms of AKI to CKD progression are still incompletely understood, making the search for new and efficient therapheutic strategies an urgent necessity
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