Key Takeaways & Executive Findings
- •• Combined BM-MSC therapy with SGLT2 inhibitor and calorie restriction significantly improved blood glucose control and reduced mesangial matrix expansion in a preclinical DKD model. • The combination therapy alleviated oxidative stress and preserved podocyte numbers, indicating a protective effect on kidney structure. • Upregulation of podocyte structural markers and RAAS renoprotective axis components suggests a mechanism for the observed renoprotection. • BAT and WAT transplantation also showed promise, offering potential alternative or adjunctive cell-based strategies for DKD management.
Abstract
Introduction The increasing prevalence of Diabetes Mellitus (DM) correlates with a rising incidence of Diabetic Kidney Disease (DKD). DKD, a multifactorial condition, is characterized by activation of the renin–angiotensin–aldosterone system (RAAS), with angiotensin II playing a significant role in podocyte injury. While conventional treatments show potential in mitigating DKD progression, a combination of strategies is required to both impede its development and repair damaged structures. Methods In this study, we explored the brown adipose tissue (BAT) and white adipose tissue (WAT) transplantation, and the use of bone marrow mesenchymal stem cell therapy (BM-MSC) combined with sodium-glucose co-transporter-2 (SGLT2) inhibitor treatment and calorie restriction in the BTBRob/ob model, recognized as a robust representation of DKD featuring hyperglycemia, obesity, time-dependent albuminuria, and histological changes. Results Our primary findings revealed enhanced blood glucose control through combined cell therapy, diminished mesangial matrix expansion, alleviated tissue oxidative stress, preserved podocyte numbers, and an upregulation of podocyte structural markers and components of the RAAS renoprotective axis. Conclusion BM-MSC therapy demonstrates considerable promise as a combined treatment for mitigating DKD progression, with similar findings observed for BAT and WAT transplantation.
1. Introduction
The global prevalence of Diabetes Mellitus (DM) is rising, with an estimated 537 million adults affected in 2019 and projections exceeding 783 million by 2045 [1]. This alarming increase is mirrored by a rise in its complications, particularly Diabetic Kidney Disease (DKD), which affects 30 to 40% of individuals with DM and is the leading cause of end-stage kidney disease (ESKD), posing a major public health challenge [2].
In DKD, dysregulation of metabolic pathways and the renin–angiotensin–aldosterone system (RAAS) synergistically contribute to podocyte injury. RAAS consists of two main axes: the ACE/Angiotensin II (Ang II)/AT1R axis, which causes inflammation, fibrosis, apoptosis, and oxidative stress; and the ACE2/Ang (1–7)/Mas axis, which has anti-inflammatory, antiapoptotic, and antifibrotic effects [3]. Chronic hyperglycemia drives aberrant intracellular glucose and lipid metabolism, generating reactive oxygen species (ROS) that induce oxidative stress. ROS primarily trigger tissue impairment by causing DNA damage, protein modification, lipid peroxidation, and disrupting cellular homeostasis, leading to apoptosis, senescence, reduced regenerative potential, and fibrosis [4].
In podocytes, hyperactivation of the RAAS further amplifies oxidative stress through Ang II-mediated activation of NADPH oxidase 4 and Transient Receptor Potential Channel 6 (TRPC6), resulting in increased cellular Ca2+ influx. This cascade culminates in podocyte cytoskeleton rearrangement and detachment, leading to increased glomerular permeability and albuminuria, hallmark features of DKD [5]. Therapeutic strategies targeting metabolic pathways, RAAS activation, and the restoration of renoprotective factors decreased in kidney diseases hold promise for mitigating podocyte injury and slowing disease progression [6]. Therefore, effective treatment requires a multifaceted approach, including lifestyle changes, blood glucose control, and drug therapies, such as RAAS inhibitors and sodium-glucose co-transporter-2 (SGLT2) inhibitors. The latter is a recently added class that acts by inhibiting sodium and glucose reabsorption in the proximal tubule. This mechanism provides both hemodynamic effects, by reestablishing tubulo-glomerular feedback and reducing hyperfiltration, and non-hemodynamic effects, by decreasing inflammation, oxidative stress, and fibrosis. Preclinical studies and clinical trials have demonstrated that SGLT2 inhibitors are associated with lower rates of decline in estimated glomerular filtration rate (eGFR), reduced proteinuria, and consequently, a slowing in DKD progression.
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Stephany Beyerstedt, Marcella L. Franco, Alanah K. G. Carlos, Jaqueline Arjona, Gleice R. Josefi-Rocha, Bruno S. Barbosa, Maria Theresa A. Balby-Rocha, Andrei Furlan da Silva, Tuany Marques Reiter Alves, Melise Oliveira Mariano, Maria Clara Soares Klein, Érika Bevilaqua Rangel (2026). Combining sodium-glucose co-transporter-2 inhibitor with mesenchymal stem cells and brown adipose tissue (BAT) and white adipose tissue (WAT) transplantation to mitigate the progression of diabetic kidney disease: a pre-clinical approach. Stem Cell Research & Therapy. https://doi.org/10.1186/s13287-025-04358-7
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Frequently Asked Questions
What is diabetic kidney disease (DKD) and why is it a major health concern?
Diabetic kidney disease is a serious complication of diabetes mellitus, affecting 30-40% of diabetic patients and is the leading cause of end-stage kidney disease. It involves progressive kidney damage due to chronic hyperglycemia and RAAS dysregulation, leading to albuminuria and decline in kidney function.
How do SGLT2 inhibitors help in diabetic kidney disease?
SGLT2 inhibitors reduce glucose reabsorption in the proximal tubule, leading to improved glycemic control and hemodynamic effects such as reduced hyperfiltration. They also have non-hemodynamic benefits including decreased inflammation, oxidative stress, and fibrosis, which slow DKD progression.
What is the role of mesenchymal stem cells (MSCs) in treating DKD?
MSCs have regenerative and immunomodulatory properties. In this study, bone marrow-derived MSCs combined with SGLT2 inhibitor and calorie restriction improved blood glucose control, reduced mesangial matrix expansion, alleviated oxidative stress, and preserved podocyte numbers, suggesting a protective effect on kidney structure.
What are the potential benefits of brown and white adipose tissue transplantation in DKD?
The study found that BAT and WAT transplantation also showed promise in mitigating DKD progression, with similar findings to MSC therapy. These approaches may offer alternative or adjunctive cell-based strategies to improve metabolic and renal outcomes.
What is the significance of the RAAS renoprotective axis in this study?
The study observed upregulation of components of the RAAS renoprotective axis (ACE2/Ang (1-7)/Mas) which has anti-inflammatory, antiapoptotic, and antifibrotic effects. This suggests that the combined therapy may shift the RAAS balance towards a protective phenotype, contributing to kidney protection.
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