Scholarship 24/08173-6 - Terapia baseada em transplante de células e tecidos, Terapia genética - BV FAPESP
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COMBINATION OF CELLULAR, GENE AND PHARMACOLOGICAL THERAPIES AS A STRATEGY TO MITIGATE PYROPTOSIS IN DIABETIC KIDNEY DISEASE

Grant number: 24/08173-6
Support Opportunities:Scholarships in Brazil - Master
Start date until: November 01, 2024
End date until: October 31, 2026
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Érika Bevilaqua Rangel
Grantee:Melise Oliveira Mariano
Host Institution: Instituto Israelita de Ensino e Pesquisa Albert Einstein (IIEPAE). Sociedade Beneficente Israelita Brasileira Albert Einstein (SBIBAE). São Paulo , SP, Brazil

Abstract

Diabetes mellitus (DM) is a global epidemic disease that is growing at an accelerated pace. According to the International Diabetes Federation, the expectation of people affected by this disease is 784 million in 2025, with more than 40% of them developing chronic kidney disease, the main cause of which is diabetic kidney disease (DKD), a specific pathology in which there is a structural and functional change in the kidneys and can cause symptoms such as proteinuria, hypertension and progressive reduction in kidney function. One of the processes that occurs in DRD is pyroptosis, a cell death that causes inflammation activated by some intra or extracellular signal and flattening of the cytoplasm due to disruption of the plasma membrane. The responsible for this process is the NLRP3 inflammasome, which is activated by several triggers, including the state of hyperglycemia, and can lead to inflammation and glomerular sclerosis in podocytes. With the progress of DM and DRD, it becomes increasingly necessary to seek alternative treatments for this disease, in order to reduce the burden on the healthcare system. Currently, therapies with both semaglutide and empagliflozin are the most relevant in the treatment of these diseases, but the cellular mechanisms involved are not fully elucidated. Furthermore, patients treated with these therapies do not show regeneration of injured renal structures. Therefore, this study aims to understand the changes in cellular pathways in DRD, the influence of therapies with semaglutide and empaglifozin on the pyroptosis pathway mediated by the NLRP3 inflammasome in podocytes in culture and BTBR ob/ob mice, and the combination of this pharmacological therapy with cell therapy using mesenchymal stem cells (MSC) genetically modified with the Klotho protein for podocyte regeneration, in order to propose an alternative to delay the progression of DRD, improving the quality and survival of patients affected by this disease.

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