Protective effect of adipose-derived mesenchymal stem cells against acute kidney injury induced by ischemia-reperfusion in Sprague-Dawley rats

Abstract Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI).The main drawbacks of MSC therapy including the lack of specific homing following systemic infusion and early death of the cells in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning promotes the therapeutic effect of the MSCs, although the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO on bone marrow mesenchymal stem cells (BMSCs) for the treatment of AKI.Results We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in the BMSCs, which was decreased following EPO pretreatment indicating that EPO protected the cells from apoptosis. Further, we found that EPO upregulated SIRT1 and Bcl-2 expression, and downregulated p53 expression. The EPO-mediated anti-apoptotic mechanism in pretreated BMSCs may be mediated though the SIRT1 pathway. In a rat AKI model, our data showed that 24 h following intravenous infusion, GFP-BMSCs were predominantly in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs, and increased the distribution of the BMSCs to the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-a and significantly higher level of IL-10 compared to rats infused with BMSCs. The administration of EPO-BMSCs after reperfusion was more effective in reducing serum creatinine, blood urea nitrogen, and pathological scores in the I/R-AKI rats than BMSCs.Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs in improving renal function and pathological presentation in I/R-AKI rats.

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PINK1 Kinase Enhances the Repair Effects of Bone Marrow Mesenchymal Stem Cells on Renal Ischemia/Reperfusion-Induced Acute Kidney Injury in Mice

10.21203/rs.3.rs-1242192/v1 ◽

2022 ◽

Author(s):

Chenyu Lin ◽

Wen Chen ◽

Yong Han ◽

Yujie Sun ◽

Xiaoqiong Zhao ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Stress Response ◽

Immune Cells ◽

Peripheral Blood ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Short Period ◽

Injured Kidney

Abstract Background: Acute kidney injury (AKI) is a common severe acute syndrome caused by multiple causes, which is characterized by a rapid decline of renal function in a short period. Bone mesenchymal stem cells (BMSCs) are effective in the treatment of AKI. However, it remains unclear about the mechanism of their beneficial effects. PENT-induced kinase 1 (PINK1) may play an important role in the kidney tissue repair. In this study, an endeavor would be made to explore the enhancing effect of PINK1 overexpression on the repair of AKI through BMSCs. Methods: In this study, the ischemia/reperfusion-induced acute kidney injury (IRI-AKI) in mice and the hypoxia-reoxygenation model of cells were established, and the indexes were detected by pathology and immunology experimental.Results: After ischemia/reperfusion, compared with the BMSCs group, the OE PINK1 group had a decreased expression of BUN, the mitigated renal fibrosis , the reduced tissue damage degree. Overexpressed PINK1 could decrease the inflammatory reaction of injured kidney tissues in IRI-AKI mice, the decreased expression of IL-10 in peripheral blood serum; and regulate the distribution of immune cells in the kidney during IRI, the decreased infiltration of lymphocytes, the increased infiltration of macrophages; and reduce the stress response of BMSCs under hypoxia and inflammation; and enhance the stress response of BMSCs to renal tubular epithelial cells(RTECs) under hypoxia and inflammation, the decreased apoptosis rate of RTECs, the decreased release of TNF-α in the cell supernatant, and the decreased proliferation of PBMCs in peripheral blood after hypoxia and reoxygenation; and regulate the autophagy of BMSCs in kidney tissues with IRI-AKI to better repair the injured kidney tissues, the increased expression of LC3-B related to autophagy and the decreased expression of mTOR.Conclusions: In this study, PINK1 overexpression enhances the repair effect of BMSCs on IRI-AKI, and the distribution of injured renal immune cells during IRI regulation by BMSCs. Besides, PINK1 enhances BMSCs and their resistance to the stress response of RTECs under hypoxia and inflammation. In addition, it regulates mitophagy during IRI-AKI. The findings of this study provide a new direction and target for the repair of IRI-AKI through BMSCs.

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Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

10.21203/rs.3.rs-17590/v3 ◽

2020 ◽

Author(s):

song zhou ◽

Yu-ming Qiao ◽

Yong-guang Liu ◽

Ding Liu ◽

Jian-min Hu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Underlying Mechanism ◽

P53 Expression ◽

Inflammatory Microenvironment ◽

Apoptotic Effect

Abstract Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect; however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment. Results We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated SIRT1 and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did. Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.

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Modulation of renal ischemia/reperfusion in rats by a combination of ischemic preconditioning and adipose-derived mesenchymal stem cells (ADMSCs)

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2016-0018 ◽

2016 ◽

Vol 94 (9) ◽

pp. 936-946 ◽

Cited By ~ 7

Author(s):

Abdelaziz M. Hussein ◽

Nashwa Barakat ◽

Amira Awadalla ◽

Mahmoud M. Gabr ◽

Sherry Khater ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Ischemic Preconditioning ◽

Caspase 3 ◽

Ischemia Reperfusion ◽

Treated Group ◽

Renal Ischemia ◽

Control Group ◽

Sprague Dawley ◽

Sprague Dawley Rats

The present study investigated the effects of combination of ischemic preconditioning (Ipre) and adipose-derived mesenchymal stem cells (ADMSCs) on renal ischemia–reperfusion (I–R) injury in rats. 90 male Sprague Dawley rats were divided into 5 equal groups; sham operated, control (45 min left renal ischemia), Ipre group as control group with 3 cycles of Ipre just before renal ischemia, ADMSCs-treated group (as control with ADMSCs 106 cells in 0.1 mL via penile vein 60 min before ischemia time), and Ipre + ADMSCs group as ADMCs group with 3 cycles of Ipre. Ipre and ADMSCs groups showed significant decrease in serum creatinine and blood urea nitrogen (BUN) and caspase-3 and CD45 expression in kidney and significant increase in HIF-1α, SDF-1α, CD31, and Ki67 expressions in kidney compared with the control group (p < 0.05). Moreover, the Ipre + ADMSCs group showed significant decrease in serum BUN and caspase-3 and CD45 expression in kidney with significant increase in HIF-1α, SDF-1α, CD31, and Ki67 expression in kidney compared with the Ipre and ADMCs groups (p < 0.05). We concluded that Ipre potentiates the renoprotective effect of ADMSCs against renal I/R injury probably by upregulation of HIF-1α, SDF-1α, CD31, and Ki67 and downregulation of caspase-3 and CD45.

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Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

10.21203/rs.3.rs-17590/v2 ◽

2020 ◽

Author(s):

song zhou ◽

Yu-ming Qiao ◽

Yong-guang Liu ◽

Ding Liu ◽

Jian-min Hu ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Underlying Mechanism ◽

Bone Mesenchymal Stem Cells ◽

P53 Expression ◽

Inflammatory Microenvironment ◽

Marrow Mesenchymal Stem Cells

Abstract Background: Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect; however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow mesenchymal stem cells (BMSCs) for AKI treatment.Results: We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated SIRT1 and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did.Conclusions: Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.

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Bone marrow derived mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

Cell & Bioscience ◽

10.1186/s13578-020-00492-2 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Song Zhou ◽

Yu-ming Qiao ◽

Yong-guang Liu ◽

Ding Liu ◽

Jian-min Hu ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Acute Kidney Injury ◽

Mesenchymal Stem Cells ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Underlying Mechanism ◽

P53 Expression ◽

Inflammatory Microenvironment ◽

Apoptotic Effect

Abstract Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI). The main drawbacks of MSCs therapy, including the lack of specific homing after systemic infusion and early cell death in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning of MSCs promotes their therapeutic effect, however, the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO in bone marrow derived mesenchymal stem cells (BMSCs) for AKI treatment. Results We found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in BMSCs, which was decreased by EPO pretreatment, indicating that EPO protected the cells from apoptosis. Further, we showed that EPO up-regulated silent information regulator 1 (SIRT1) and Bcl-2 expression and down-regulated p53 expression. This effect was partially reversed by SIRT1 siRNA intervention. The anti-apoptotic effect of EPO in pretreated BMSCs may be mediated through the SIRT1 pathway. In a rat AKI model, 24 h after intravenous infusion, GFP-BMSCs were predominantly located in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs and increased their distribution in the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-α, and a significantly higher level of IL-10 as compared to rats infused with untreated BMSCs. The administration of EPO-BMSCs after reperfusion reduced serum creatinine, blood urea nitrogen, and pathological scores in I/R-AKI rats more effectively than BMSCs treatment did. Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs to improve the renal function and pathological presentation of I/R-AKI rats.

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Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00339.2006 ◽

2007 ◽

Vol 292 (5) ◽

pp. F1626-F1635 ◽

Cited By ~ 432

Author(s):

Florian Tögel ◽

Kathleen Weiss ◽

Ying Yang ◽

Zhuma Hu ◽

Ping Zhang ◽

...

Keyword(s):

Stem Cells ◽

Acute Kidney Injury ◽

Blood Flow ◽

Mesenchymal Stem Cells ◽

Conditioned Medium ◽

Expression Profiles ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Cell Phenotype ◽

Paracrine Actions

Acute kidney injury (AKI) is a major clinical problem in which a critical vascular, pathophysiological component is recognized. We demonstrated previously that mesenchymal stem cells (MSC), unlike fibroblasts, are significantly renoprotective after ischemia-reperfusion injury and concluded that this renoprotection is mediated primarily by paracrine mechanisms. In this study, we investigated whether MSC possess vasculoprotective activity that may contribute, at least in part, to an improved outcome after ischemia-reperfusion AKI. MSC-conditioned medium contains VEGF, HGF, and IGF-1 and augments aortic endothelial cell (EC) growth and survival, a response not observed with fibroblast-conditioned medium. MSC and EC share vasculotropic gene expression profiles, as both form capillary tubes in vitro on Matrigel alone or in cooperation without fusion. MSC undergo differentiation into an endothelial-like cell phenotype in culture and develop into vascular structures in vivo. Infused MSC were readily detected in the kidney early after reflow but were only rarely engrafted at 1 wk post-AKI. MSC attached in the renal microvascular circulation significantly decreased apoptosis of adjacent cells. Infusion of MSC immediately after reflow in severe ischemia-reperfusion AKI did not improve renal blood flow, renovascular resistance, or outer cortical blood flow. These data demonstrate that the unique vasculotropic, paracrine actions elicited by MSC play a significant renoprotective role after AKI, further demonstrating that cell therapy has promise as a novel intervention in AKI.

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