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Evaluation of the transcript level of the CD2AP gene after albumin overload in podocytes in vitro

Grant number: 22/03907-6
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2022
Effective date (End): December 31, 2023
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Mara Sanches Guaragna
Grantee:José Ronaldo Alves Troleze
Host Institution: Centro de Biologia Molecular e Engenharia Genética (CBMEG). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

The presence of persistent proteinuria is the main sign of glomerular disease and the development of chronic kidney disease (CKD) is an important prognostic marker for this condition. In glomerular injury, the main protein present in the urine is albumin. In this case, albuminuria results from impairment of the glomerular filtration barrier, which may be associated with podocyte injury. Podocytes are highly specialized and differentiated cells, whose extensions, the foot processes, are extremely important in the filtration process and are divided into three domains: apical membrane domain (AMD), slit diaphragm (SD), and basal membrane domain (BMD). Damage to these domains leads to a characteristic response, foot process effacement, which leads to progressive albuminuria. However, there are still controversies in the literature regarding the impact of proteinuria on foot process effacement in podocytopathies. There are a few studies in the literature evaluating the impact of albumin overload on podocyte cell culture in vitro, showing alterations in pathways related to inflammation, reticulum stress, apoptosis, proliferation, cell differentiation, and cytoskeletal rearrangement. Despite having achieved good results, these previous studies still do not definitively clarify the molecular consequences of albumin overload. Several proteins are involved in the maintenance of podocyte structure and function and can affect the actin cytoskeleton rearrangement, CD2AP is one of them. One study showed the downregulation of CD2AP after albumin overload in murine podocytes in vitro. However, it was not verified the effect of removing albumin on phenotype recovery. Furthermore, the evaluation of the albumin effect was performed only on podocytes without previous damage. Therefore, the objective of the present study is to evaluate whether there is a difference in expression of CD2AP gene after progressive albumin overload in human podocytes in vitro, and, if there is any change, regression of the overload will be performed to verify the recovery of the phenotype. Moreover, we will also evaluate the effect of albumin overload on podocytes with previous exposure to the nephrotoxic drug puromycin aminoglycoside (PAN). Finally, we will evaluate the ability of adhesion of podocytes, in the same conditions. It is important to point out that the advancement of knowledge of specific molecular pathways could allow the identification of potential therapeutic targets for general or specific conditions. If successful, such future studies could propose the use of interventions capable of minimizing the deleterious renal effects of albumin, contributing to the deceleration of CKD progression in many patients.(AU)

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