Bone Marrow-Derived Mononuclear Cells Promote Improvement in Glomerular Function in Rats with Early Diabetic Nephropathy

Castiglione, Raquel C.; Maron‐Gutierrez, Tatiana; Barbosa, Carolina; Ornellas, Felipe M.; Barreira, André Luis; Dibarros, Carolina B A; Vasconcelos-dos-Santos, Andréia; Paredes, Bruno Diaz; Pascarelli, Bernardo Miguel de Oliveira; Diaz, Bruno L.; Rossi-Bergmann, Bartira; Takiya, Christina Maeda; Rocco, Patrícia Rieken Macêdo; Souza-Menezes, Jackson; Morales, Marcelo M.

doi:10.1159/000354473

Cited by 14 publications

(14 citation statements)

References 70 publications

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“…7A–B) compared with animals in the control group. On the other hand, the decrease in tubular cell apoptosis, also found here in the IR-C group, corroborates the cytoprotective effect of cell therapy; diminution of the apoptotic levels could have reestablished equilibrium in the kinetics of the tubular compartment This improvement induced by BMMCs has been already been shown in several acute and chronic models of disease after diverse kinds of cell therapy [13-15, 71] and seems to be due to the production of pro-survival growth factors [72-74]. …”

Section: Discussionsupporting

confidence: 81%

“…Thereafter, BMMCs were injected as previously reported [15]. Bone marrow cells were aspirated by flushing the bone marrow cavity with Dulbecco's modified Eagle's medium (Life Technologies, Grand Island, NY).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were counted in a Neubauer chamber with trypan blue for evaluation of viability. The BMMC population from Wistar rats used in the experiments was previously characterized by flow cytometry as described by Castiglione et al [15]. …”

Section: Methodsmentioning

confidence: 99%

“…As cell-based therapies based on bone marrow–derived mononuclear cells (BMMCs) were the first to be used, their effects, security, and failures are now widely known. Despite their promising results to improve structural recovery, complete functional improvement has still not been achieved [13-15]. Different from other types of cell therapies, therapy with BMMCs consists of a mixture of lymphoid, myeloid, erythroid, and stem cell populations, and specifically in humans, of T cells, B cells, monocytes, natural killer cells, and hematopoietic progenitor cells [16, 17].…”

Section: Introductionmentioning

confidence: 99%

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Bone Marrow–Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules

Ornellas¹,

Ornellas²,

Martini³

et al. 2017

Cell Physiol Biochem

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Background/Aims: We investigated the regenerative capacity of intravenous administration of bone marrow–derived mononuclear cells (BMMCs) in a rat model of bilateral renal ischemia/reperfusion (IR) injury and the involvement of inflammatory anti-inflammatory and other biological markers in this process. Methods: Rats were subjected to 1h bilateral renal pedicle clamping. BMMCs were injected i.v 1h after reperfusion and tracked by ^99mTc and GFP+ BMMCs. Twenty-four hours after reperfusion, renal function and histological changes were evaluated. The mRNA (real time PCR) and protein (ELISA and immuno-staining) expression of biological markers were analyzed. Results: Renal function and structure improved after infusion of BMMCs in the IR group (IR-C). Labeled BMMCs were found in the kidneys after therapy. The expression of inflammatory and biological markers (TLR-2, TRL-4, RAGE, IL-17, HMGB-1, KIM-1) were reduced and the expression of anti-inflammatory and antioxidant markers (IL-10, Nrf2, and HO-1) were increased in IR-C animals compared with IR untreated animals (IR-S). The apoptotic index diminished and the proliferation index increased in IR-C compared with IR-S. Conclusion: The results contribute to our understanding of the role of different biological players in morphofunctional renal improvement and cytoprotection in a post-ischemic reperfusion kidney injury model subjected to cellular therapy.

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Section: Discussionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bone Marrow–Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules

Ornellas¹,

Ornellas²,

Martini³

et al. 2017

Cell Physiol Biochem

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“…2013; Betz and Conway 2014). A single dose of STZ is not toxic to the kidney or to the proximal tubule, as shown previously by Palm et al.…”

Section: Discussionmentioning

confidence: 99%

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

et al. 2017

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Diabetic nephropathy (DN) occurs in around 40% of those with diabetes. Proteinuria is the main characteristic of DN and develops as a result of increased permeability of the glomerulus capillary wall and/or decreased proximal tubule endocytosis. The goal of this work was to evaluate renal function and the expression of megalin, cubilin, CFTR (cystic fibrosis transmembrane conductance regulator), and ClC‐5 in the proximal tubule and renal cortex of rats with type 1 diabetes. Male Wistar rats were randomly assigned to control (CTRL) and diabetic (DM) groups for 4 weeks. Renal function was assessed in 24‐h urine sample by calculating clearance and fractional excretion of solutes. The RNA and protein contents of ClC‐5, CFTR, megalin, and cubilin were determined in the renal proximal tubule and cortex using real‐time polymerase chain reaction and western blotting techniques, respectively. The results showed higher creatinine clearance and higher urinary excretion of proteins, albumin, and transferrin in the DM group than in the CTRL group. Furthermore, the renal cortex and proximal tubule of diabetic animals showed downregulation of megalin, cubilin, ClC‐5, and CFTR, critical components of the endocytic apparatus. These data suggest dysfunction in proximal tubule low‐molecular‐weight endocytosis and protein glomerulus filtration in the kidney of diabetic rats.

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A Systematic Review and Meta-Analysis of Cell-Based Interventions in Experimental Diabetic Kidney Disease

Hickson

Abedalqader

Ben-Bernard

et al. 2021

Stem Cells Translational Medicine

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Regenerative, cell-based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta-analysis summarized the effect of cell-based interventions in DKD animal models and treatment-related factors modifying outcomes. Electronic databases were searched for original investigations applying cell-based therapy in diabetic animals with kidney endpoints (January 1998-May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random-effects models. Subgroup analyses tested treatment-related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non-MSC (15%), and cell-derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell-based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial-mesenchymal-transition, oxidative stress). Preconditioning, xenotransplantation, and disease-source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell-based interventions in diabetic animals improved kidney function and reduced injury with treatment-related factors Authored by a member of IFATS.

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Bone Marrow-Derived Mononuclear Cells Promote Improvement in Glomerular Function in Rats with Early Diabetic Nephropathy

Cited by 14 publications

References 70 publications

Bone Marrow–Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules

Bone Marrow–Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules

Diabetic rats present higher urinary loss of proteins and lower renal expression of megalin, cubilin, ClC-5, and CFTR

A Systematic Review and Meta-Analysis of Cell-Based Interventions in Experimental Diabetic Kidney Disease

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