BackgroundIt is confirmed that adipose-derived stem cells (ADSCs) transplantation effectively relieves kidney fibrosis and type 2 diabetes disease in mice. Currently, exosome from urine-derived stem cells (USCs) can protect type 1 diabetes-mediated kidney injury and attenuate podocyte damage in diabetic nephropathy (DN). Exosome derived from USCs has evolved into the strategy for DN treatment, but the role of ADSCs-derived exosome (ADSCs-Exo) in DN remains unclear. The present study is aimed to investigate the therapeutic action and molecular mechanism of ADSCs-derived exosome on DN.MethodsADSCs and exosome were authenticated by immunofluorescence and flow cytometry. Morphology and the number of exosome were evaluated by electron microscope and Nanosight Tracking Analysis (NTA), respectively. Cell apoptosis was assessed using flow cytometry. Podocyte autophagy and signaling transduction were measured by immunofluorescence and immunoblotting. Dual Luciferase Reporter assay was employed to detect the regulatory relationship between miR-486 and Smad1.ResultsADSCs-Exo attenuated spontaneous diabetes by reducing levels of urine protein, serum creatinine (Scr), blood urea nitrogen (BUN), and podocyte apoptosis in mice. In in vitro experiment, ADSCs-Exo also reversed high glucose-induced decrease of cell viability and the increase of cell apoptosis in MPC5 cells. In terms of mechanism, ADSCs-Exo could enhance autophagy flux and reduce podocyte injury by inhibiting the activation of mTOR signaling in MPC5 and spontaneous diabetic mice. Eventually, we found that miR-486 was the key factors in ADSCs and in the process of ADSCs-Exo-mediated improvement of DN symptom in vivo and in vitro. miR-486 reduced Smad1 expression by target regulating Smad1 whose reduction could inhibit mTOR activation, leading to the increase of autophagy and the reduction of podocyte apoptosis.ConclusionsIn conclusion, we illustrated that ADSCs-Exo vividly ameliorated DN symptom by enhancing the expression of miR-486 which led to the inhibition of Smad1/mTOR signaling pathway in podocyte. Possibly, ADSCs-Exo was used as a main therapeutic strategy for DN in future.Electronic supplementary materialThe online version of this article (10.1186/s13287-019-1177-1) contains supplementary material, which is available to authorized users.
Cancer patients have a high risk for acute kidney injury (AKI); however, the incidence, severity, and risk factors of malignancy-related AKI (MR-AKI) are unclear. This study aimed to assess MR-AKI risk factors and provide reliable data for AKI prevention, diagnosis, and management in China. This cross-sectional study analysed data from 44 academic and local hospitals in China. AKI patients were identified based on 2 screening criteria: the 2012 Kidney Disease: Improving Global Outcomes-AKI definition and the expanded screening criteria for patients with no repeated serum creatinine (SCr) test within 7 days and those who recovered from AKI. Patients whose SCr level increased or decreased by 50% during hospitalization, compared with that at admission, were considered to have AKI according to the expanded criteria. A total of 7,604 AKI patients were enrolled (1,418 with MR-AKI). Patient characteristics were compared between the MR-AKI and non-MR-AKI groups. Multivariate logistic models were used to statistically assess risk factors. The proportions of MR-AKI patients in academic and local hospitals were 20.2% and 14.1%, respectively. The incidence of MR-AKI was higher in mid-China (the affluent region), elderly patients, and groups with higher per capita gross domestic product. Among MR-AKI cases, gastrointestinal cancer (50.1%) was the most common malignancy, followed by cancers of the reproductive (15.3%), haematological (13.1%), respiratory (11.8%), and other systems (8.3%), and cancers of unknown classification (1.4%). Of 268 hospital deaths, respiratory, haematological, gastrointestinal, reproductive, other system, and unknown classification cancers accounted for 29.3%, 18.8%, 18.6%, 12.9%, 16.9%, and 20.0%, respectively. Increased age, advanced AKI stage at peak, level of per capita gross domestic product, geographic region, and renal replacement therapy indication were risk factors for hospital mortality in patients with gastrointestinal MR-AKI, whereas cardiovascular disease history, AKI stage at peak, and geographic region were risk factors for mortality in patients with reproductive MR-AKI. The incidence and mortality of MR-AKI vary by hospital, economic level, age, geographic region, and malignancy type. High MR-AKI incidence was associated with gastrointestinal cancers and higher level of medical care provided by academic hospitals in affluent regions such as Beijing, Shanghai, and other provincial-level cities. Elderly patients with advanced gastrointestinal cancer in mid-China showed the highest incidence of MR-AKI and in-hospital mortality, and thus require special attention.
Background: Renal fibrosis is a chronic and progressive process affecting kidneys in chronic kidney disease (CKD). Mesenchymal stem cells-derived exosomes (MSCs-Exo) have been shown to alleviate renal fibrosis and injury, but the mechanism of MSCs-Exoinduced renal protection remains unknown. Methods: In this study, MSCs were transfected with let-7i-5p antagomir (anti-let-7i-5p), and then exosomes were isolated from the transfected MSCs to deliver anti-let-7i-5p oligonucleotides to inhibit the level of let-7i-5p in kidney tubular epithelial cells (NRK-52E). Results: In both NRK-52E cells stimulated by TGF-β1 and the mouse kidneys after unilateral ureteral obstruction (UUO), we demonstrated increased level of let-7i-5p. In addition, MSCs-Exo can deliver anti-let-7i-5p to reduce the level of let-7i-5p in NRK-52E cells and increase the expression of its target gene TSC1. Moreover, exosomal anti-let-7i-5p reduced extracellular matrix (ECM) deposition and attenuated epithelial-mesenchymal transition (EMT) process in transforming growth factor beta 1 (TGF-β1)-stimulated NRK-52E cells and in the kidneys of UUO-treated mice. Meanwhile, mice received exosomal anti-let -7i-5p displayed reduced renal fibrosis and improved kidney function when challenged with UUO. Furthermore, exosomal anti-let-7i-5p promoted the activation the tuberous sclerosis complex subunit 1/mammalian target of rapamycin (TSC1/mTOR) signaling pathway in vivo and in vitro. Conclusion:In conclusion, exosomal anti-let-7i-5p from MSCs exerts anti-fibrotic effects in TGF-β1-induced fibrogenic responses in NRK52E cells in vitro as well as in UUOinduced renal fibrosis model in vivo. These results provided a novel perspective on improving renal fibrosis by MSCs-Exo.
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