Therapeutic Potential of Mesenchymal Stem Cells in a Pre-Clinical Model of Diabetic Kidney Disease and Obesity

Author(s)

Savio-Silva, Christian ^[1] ; Soinski-Sousa, Poliana E. ^[1] ; Simplicio-Filho, Antonio ^[1] ; Bastos, Rosana M. C. ^[1] ; Beyerstedt, Stephany ^[1] ; Rangel, Erika Bevilaqua ^{[1, 2]}

Affiliation

^[1] Hosp Israelita Albert Einstein, BR-05652900 Sao Paulo - Brazil

^[2] Univ Fed Sao Paulo, Escola Paulista Med, Nephrol Div, BR-04023900 Sao Paulo - Brazil

• Document type: Journal article
• Source: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES; v. 22, n. 4 FEB 2021.
• Web of Science Citations: 0

Abstract

Diabetic kidney disease (DKD) is a worldwide microvascular complication of type 2 diabetes mellitus (T2DM). From several pathological mechanisms involved in T2DM-DKD, we focused on mitochondria damage induced by hyperglycemia-driven reactive species oxygen (ROS) accumulation and verified whether mesenchymal stem cells (MSCs) anti-oxidative, anti-apoptotic, autophagy modulation, and pro-mitochondria homeostasis therapeutic potential curtailed T2DM-DKD progression. For that purpose, we grew immortalized glomerular mesangial cells (GMCs) in hyper glucose media containing hydrogen peroxide. MSCs prevented these cells from apoptosis-induced cell death, ROS accumulation, and mitochondria membrane potential impairment. Additionally, MSCs recovered GMCs' biogenesis and mitophagy-related gene expression that were downregulated by stress media. In BTBRob/ob mice, a robust model of T2DM-DKD and obesity, MSC therapy (1 x 10(6) cells, two doses 4-weeks apart, intra-peritoneal route) led to functional and structural kidney improvement in a time-dependent manner. Therefore, MSC-treated animals exhibited lower levels of urinary albumin-to-creatinine ratio, less mesangial expansion, higher number of podocytes, up-regulation of mitochondria-related survival genes, a decrease in autophagy hyper-activation, and a potential decrease in cleaved-caspase 3 expression. Collectively, these novel findings have important implications for the advancement of cell therapy and provide insights into cellular and molecular mechanisms of MSC-based therapy in T2DM-DKD setting. (AU)

• FAPESP's process: 17/23195-2 - Mesenchymal stem cell therapy for halting the progression of acute and chronic kidney injury and in vivo modulate kidney-derived c-Kit stem cells
• Grantee: Érika Bevilaqua Rangel
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/24562-1 - Evaluation of oxidative stress and cell death of renal cells conditioned in vitro to Diabetic Renal Disease after treatment with bone marrow mesenchymal stem cells transfected with the Klotho gene
• Grantee: Poliana Evelyn Soinski de Sousa
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• FAPESP's process: 17/18072-9 - Glomerular mesangial cells mitochondrial dynamics alterations in hyperglycemia followed by mesenchymal stem cell therapy
• Grantee: Christian Sávio Silva
• Support Opportunities: Scholarships in Brazil - Master