Multi-target therapy in diabetic kidney disease and acute kidney injury: mesenchymal stem cells, klotho, empagliflozin, and semaglutide

• Grant number: 24/08725-9
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2026
• End date: January 31, 2029
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Érika Bevilaqua Rangel
• Grantee: Érika Bevilaqua Rangel
• Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). São Paulo , SP, Brazil
• City of the host institution: São Paulo
• Associated researchers: Joshua M Hare ; LUCIANA CINTRA ; Samirah Abreu Gomes

Abstract

Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease worldwide. It is associated with high morbidity and mortality rates, particularly due to micro- and macroangiopathic complications. In this context, there is a significant impact on quality of life and a burden on the healthcare system. In addition to previously established non-pharmacological approaches, several therapeutic pillars have been proposed as strategies to slow DKD progression. Among these pillars, the renin-angiotensin-aldosterone system blockade, the use of sodium-glucose co-transporter-2 inhibitors (SGLT2i), and glucagon-like peptide-1 receptor agonists (GLP-1RA) stand out. However, since multiple metabolic, hemodynamic, and inflammatory pathways are involved in the underlying pathophysiology of DKD, we emphasize the need for the advancement of multitarget therapies to halt disease progression.In this regard, glycemic overload leads to the dysregulation of several metabolic pathways (polyol, hexosamine, advanced glycation end products, and protein kinase C), resulting in oxidative stress, mitochondrial dysfunction, and cell death, in addition to inflammation, senescence, and fibrosis. The current project aims to investigate the use of two pharmacological therapeutic approaches (the SGLT2 inhibitor empagliflozin and the GLP-1 receptor agonist semaglutide), already established as strategies to delay DKD progression in humans, and assess their impact on dysregulated signaling pathways in DKD, particularly pyroptotic cell death. Furthermore, we will evaluate the therapeutic efficacy of other multitarget therapies, such as allogeneic mesenchymal stem cell therapy and gene therapy based on klotho overexpression, combined with pharmacological treatments.We will use leptin knockout animals (BTBR ob/ob), which present hyperphagia, type 2 diabetes mellitus, obesity, and time-dependent progressive DKD, resembling alterations observed in humans. Treatment using empagliflozin and semaglutide will be implemented, in combination with cell and klotho gene therapies. We will evaluate functional outcomes (weight, blood glucose, albuminuria, and glomerular filtration rate), structural outcomes (mesangial expansion, glomerular area, podocyte count, macrophage infiltration, pancreatic islet morphology), and the signaling pathway related to pyroptotic cell death mediated by the inflammasome through molecular and cellular biology assays.In vitro assays using immortalized murine podocytes will allow us to assess the impact of pharmacological, cell, and gene therapies on pyroptotic cell death through analysis of IL-1¿ and IL-18. To understand the interaction between acute kidney injury (AKI) and DKD in BTBR ob/ob and cKit;mTmG mice subjected to glycerol-induced rhabdomyolysis, we will investigate whether empagliflozin exerts a renoprotective effect to mitigate kidney damage. We will assess renal function and albuminuria, kidney morphology, signaling pathways of pyroptotic cell death and inflammation, as well as the modulation of the renal tissue-specific c-Kit+ stem/progenitor cell pool.In summary, we intend to explore the therapeutic potential of combined approaches-including pharmacological, cell, and gene therapies-that exhibit multitarget properties in metabolic, hemodynamic, and inflammatory pathways, aiming to synergistically reduce DKD progression and attenuate AKI impact in the DKD setting. Our findings may therefore contribute to future human studies and advance knowledge in the kidney protection-renal regeneration axis. (AU)