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BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

ABSTRACT: Introduction: Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. Methods: In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatment. Results: Our results showed that STZ-induced DN rats had extensive histopathological changes, significant upregulation in mRNA expression of renal apoptotic markers, ER stress markers, inflammatory markers, fibronectin, and intermediate filament proteins, and reduction of positive immunostaining of PCNA and elevated P53 in kidney tissue compared to the control group. BM-MSC therapy significantly improved renal histopathological changes, reduced renal apoptosis, ER stress, inflammation, and intermediate filament proteins, as well as increased positive immunostaining of PCNA and reduced P53 in renal tissue compared to the STZ-induced DN group. Conclusion: In conclusion, our study indicates that BM-MSCs may have therapeutic potential for the treatment of DN and provide important insights into their potential use as a novel therapeutic approach for DN.

SUBMITTER: Khamis T

PROVIDER: S-EPMC10690373 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Khamis Tarek T Abdelkhalek Adel A Abdellatif Hussein H Dwidar Nourelden N Said Ahmed A Ahmed Rama R Wagdy Kerolos K Elgarhy Rowina R Eltahan Rawan R Mohamed Hisham H Said Amer Eman E Hanna Maria M Ragab Tarek T Kishk Abdallah A Wael Judy J Sarhan Eyad E Saweres Linda L Reda Mohamed M Elkomy Sara S Mohamed Abdalah A Samy Abdullah A Khafaga Ateya A Shaker Youliana Y Yehia Hamdy H Alanazi Asma A Alassiri Mohammed M Tîrziu Emil E Bucur Iulia Maria IM Arisha Ahmed Hamed AH

Frontiers in pharmacology 20231116

<b>Introduction:</b> Diabetic nephropathy (DN), a chronic kidney disease, is a major cause of end-stage kidney disease worldwide. Mesenchymal stem cells (MSCs) have become a promising option to mitigate several diabetic complications. <b>Methods:</b> In this study, we evaluated the therapeutic potential of bone marrow-derived mesenchymal stem cells (BM-MSCs) in a rat model of STZ-induced DN. After the confirmation of diabetes, rats were treated with BM-MSCs and sacrificed at week 12 after treatm ...[more]

PMID: 38044936

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Project description:BackgroundThe microRNA-30 family plays a critical role in the pathogenesis of podocyte injury. Cx43 plays an essential role in intercellular communication, which is essential for coordinated kidney function. This study was conducted to explore the function of microRNA-30s/Cx43 in podocyte injury in diabetic nephropathy (DN), both in vivo and in vitro.MethodsSD rats were given streptozotocin (STZ) injections to induce DN. Podocytes were incubated in the medium in the presence or absence of high glucose (HG). The effects of the microRNA-30/Cx43 axis on DN and its underlying mechanisms were investigated by TUNEL assay, PAS, immunohistochemical staining, immunofluorescence staining, Western blot, RT-qPCR, RNA interference, and luciferase reporter assay. Podocytes were transfected with microRNA-30 family mimics, microRNA-30 family inhibitors, Cx43 siRNA, and negative controls to detect the effect of the microRNA-30/Cx43 axis. MicroRNA-30 family mimic AAVs, and microRNA-30 family inhibitor AAVs applied to regulate microRNA-30 family expression in the kidneys of the STZ-induced DN model rats to reveal the underlying mechanisms of the microRNA-30/Cx43 axis in DN.ResultsMicroRNA-30 family member expression was downregulated in HG-treated podocytes and the glomeruli of STZ-induced DN rats. Luciferase reporter assays confirmed Cx43 is a directed target of microRNA-30s. The overexpression of microRNA-30 family members attenuated the HG-induced podocyte injury and protected against podocyte apoptosis and endoplasmic reticulum stress (ERS) both in vivo and in vitro. Also, silencing Cx43 expression eased podocyte apoptosis, injury, and ERS induced by a HG+microRNA-30 family inhibitor. Double-immunofluorescence staining assays proved the co-localization of caspase12 and Cx43.ConclusionsThe overexpression of microRNA-30 family members prevents HG-induced podocyte injury and attenuates ERS by modulating Cx43 expression. The microRNA-30/Cx43/ERS axis might be a potential therapeutic target to treat DN.

Project description:BackgroundRadiotherapy to cancer patients is inevitably accompanied by normal tissue injury, and the bone is one of the most commonly damaged tissues. Damage to bone marrow mesenchymal stem cells (BM-MSCs) induced by radiation is thought to be a major cause of radiation-induced bone loss. Exosomes exhibit great therapeutic potential in the treatment of osteoporosis, but whether exosomes are involved in radiation-induced bone loss has not been thoroughly elucidated to date. The main purpose of this study is to investigate the role of exosomes derived from BM-MSCs in restoring recipient BM-MSC function and alleviating radiation-induced bone loss.MethodsBM-MSC-derived exosomes were intravenously injected to rats immediately after irradiation. After 28 days, the left tibiae were harvested for micro-CT and histomorphometric analysis. The effects of exosomes on antioxidant capacity, DNA damage repair, proliferation, and cell senescence of recipient BM-MSCs were determined. Osteogenic and adipogenic differentiation assays were used to detect the effects of exosomes on the differentiation potential of recipient BM-MSCs, and related genes were measured by qRT-PCR and Western blot analysis. β-Catenin expression was detected at histological and cytological levels.ResultsBM-MSC-derived exosomes can attenuate radiation-induced bone loss in a rat model that is similar to mesenchymal stem cell transplantation. Exosome-treated BM-MSCs exhibit reduced oxidative stress, accelerated DNA damage repair, and reduced proliferation inhibition and cell senescence-associate protein expression compared with BM-MSCs that exclusively received irradiation. Following irradiation, exosomes promote β-catenin expression in BM-MSCs and restore the balance between adipogenic and osteogenic differentiation.ConclusionsOur findings indicate that BM-MSC-derived exosomes take effects by restoring the function of recipient BM-MSCs. Therefore, exosomes may represent a promising cell-free therapeutic approach for the treatment of radiation-induced bone loss.

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BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

Publications

BM-MSCs alleviate diabetic nephropathy in male rats by regulating ER stress, oxidative stress, inflammation, and apoptotic pathways.

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