The Role of Bone Marrow Cells in the Phenotypic Changes Associated with Diabetic Nephropathy

PLOS ONE, Dec 2019

The aim of our study was to investigate the role of bone marrow cells in the phenotypic changes that occur in diabetic nephropathy. Bone marrow cells were obtained from either streptozotocin-induced diabetic or untreated control C3H/He mice and transplanted into control C3H/He mice. Eight weeks after bone marrow cell transplantation, renal morphologic changes and clinical parameters of diabetic nephropathy, including the urine albumin/creatinine ratio and glucose tolerance, were measured in vivo. Expression levels of the genes encoding α1 type IV collagen and transforming growth factor-β1 in the kidney were assayed. Our results demonstrated that glucose tolerance was normal in the recipients of bone marrow transplants from both diabetic and control donors. However, compared with recipients of the control bone marrow transplant, the urinary albumin/creatinine ratio, glomerular size, and the mesangial/glomerular area ratio increased 3.3-fold (p < 0.01), 1.23-fold (p < 0.01), and 2.13-fold (p < 0.001), respectively, in the recipients of the diabetic bone marrow transplant. Expression levels of the genes encoding glomerular α1 type IV collagen and transforming growth factor-β1 were also significantly increased (p < 0.01) in the recipients of the diabetic bone marrow transplant. Our data suggest that bone marrow cells from the STZ-induced diabetic mice can confer a diabetic phenotype to recipient control mice without the presence of hyperglycemia.

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The Role of Bone Marrow Cells in the Phenotypic Changes Associated with Diabetic Nephropathy

September The Role of Bone Marrow Cells in the Phenotypic Changes Associated with Diabetic Nephropathy Guang Yang 0 1 Qingli Cheng 0 1 Sheng Liu 0 1 Jiahui Zhao 0 1 0 Department of Geriatric Nephrology, Chinese People's Liberation Army General Hospital, State Key Laboratory of Kidney Disease , Beijing , China 1 Editor: Paolo Fiorina, Children's Hospital Boston/ Harvard Medical School , UNITED STATES The aim of our study was to investigate the role of bone marrow cells in the phenotypic changes that occur in diabetic nephropathy. Bone marrow cells were obtained from either streptozotocin-induced diabetic or untreated control C3H/He mice and transplanted into control C3H/He mice. Eight weeks after bone marrow cell transplantation, renal morphologic changes and clinical parameters of diabetic nephropathy, including the urine albumin/ creatinine ratio and glucose tolerance, were measured in vivo. Expression levels of the genes encoding α1 type IV collagen and transforming growth factor-β1 in the kidney were assayed. Our results demonstrated that glucose tolerance was normal in the recipients of bone marrow transplants from both diabetic and control donors. However, compared with recipients of the control bone marrow transplant, the urinary albumin/creatinine ratio, glomerular size, and the mesangial/glomerular area ratio increased 3.3-fold (p < 0.01), 1.23fold (p < 0.01), and 2.13-fold (p < 0.001), respectively, in the recipients of the diabetic bone marrow transplant. Expression levels of the genes encoding glomerular α1 type IV collagen and transforming growth factor-β1 were also significantly increased (p < 0.01) in the recipients of the diabetic bone marrow transplant. Our data suggest that bone marrow cells from the STZ-induced diabetic mice can confer a diabetic phenotype to recipient control mice without the presence of hyperglycemia. - Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by the National Natural Science Foundation of China (81170312, 30772296) (http://www.nsfc.gov.cn), and the National Natural Science Foundation of Beijing (7122163) (http://www.bjkw.gov.cn/n8785584/index.html) granted to QC. The funders had participated in study design, data collection and analysis, decision to publish, and preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The prevalence of chronic kidney disease in China is 10.8%. Diabetes is one of the risk factors independently associated with chronic kidney disease [1]. About 25% to 40% of patients with diabetes will develop diabetic nephropathy (DN), characterized by histological changes or a progressive decline in the glomerular filtration rate, within 20 to 25 years of the onset of type 1 or type 2 diabetes mellitus. ECM accumulation and mesangial cell proliferation are pathologic hallmarks or phenotypic changes associated with DN [2]. Hyperglycemia has been implicated in the development of the phenotypic changes associated with DN [3]. Several mechanisms contribute to these phenotypic changes, including high mitochondrial oxidative stress, metabolic pathways, chronic inflammation, immune-related podocyte injury and participation of cytokines [3–5]. However, the Diabetes Control and Complications Trial observed that some patients are resistant to DN development despite years of poor blood glucose control, whereas 26% of the patients still progressed to DN despite adequate blood glucose control. These observations indicated that other factors, in addition to hyperglycemia, contribute to the progression of DN [6]. Mesenchymal stem cells, also known as multipotent mesenchymal stromal cells, are selfrenewing cells that can be found in almost all postnatal organs and tissues. Mesenchymal stem cells are most frequently isolated from bone marrow (BM) and are also known as BM stem cells. It has been previously demonstrated that BM stem cells contribute to renal regeneration in animal models of DN. Moreover, the function of BM stem cells may be affected by hyperglycemia associated with diabetes [7]. A previous study demonstrated that naive syngeneic B6 mice developed albuminuria and severe glomerular lesions in the absence of hyperglycemia when transplanted with BM cells from db/db mice with established DN [8]. However, the db/ db mouse is a spontaneous diabetic model; thus, it is difficult to identify whether the DN phenotypic changes were induced by genetic factors or were acquired characteristics of BM cells. To elucidate the role of BM cells in the phenotypic changes associated with diabetic nephropathy, the genetic components of diabetes should be excluded from the animal model. To determine whether C3H/He mice were vulnerable to hyperglycemia, the effects of high ambient glucose concentrations on mesangial cells isolated from C3H/He and C57BL/6 mice were compared. In addition, we established a streptozotocin (ST (...truncated)


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Guang Yang, Qingli Cheng, Sheng Liu, Jiahui Zhao. The Role of Bone Marrow Cells in the Phenotypic Changes Associated with Diabetic Nephropathy, PLOS ONE, 2015, 9, DOI: 10.1371/journal.pone.0137245