Epigenetic regulation of TET and Klotho proteins in Glomerular Disease

• Grant number: 19/10583-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: September 01, 2020
• End date: August 01, 2024
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Karina Thieme
• Grantee: Beatriz Maria Veloso Pereira
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/00573-4 - The role of DNA (hydroxy)methylation in podocytes dysfunction: epigenetic perspectives for the treatment of Chronic Kidney Disease, AP.JP
• Associated scholarship(s): 22/00073-7 - Podocyte adversely impact the health of neighboring parietal epithelial cells in the aged kidney, BE.EP.DR

Abstract

Chronic Kidney Disease (CKD) is a clinical condition characterized by progressive loss of kidney function and persistent presence of proteins in the urine. Among the causes that can lead to CKD are glomerulopathies, especially Focal Segmental Glomerulosclerosis (FSGS). Loss of protein in the urine and development of FSGS is closely associated with dysfunction and loss of podocytes, specialized cells that compose the glomerular filtration barrier. Because they are highly differentiated and not proliferative cells, their loss is irreversible. Knowing that the existing therapies for the treatment of FSGS are not effective, the search for new therapeutic targets that can prevent the loss of podocytes and consequently the progress towards CKD are extremely relevant and necessary. In this context, molecules with nephroprotective properties, such as Klotho protein, have been highlighted. Among its functions is the modulation of pathways related to renal injury such as pro-fibrotic pathway, Epithelial-Mesenchymal Transition (EMT), oxidative stress and autophagy. Interestingly, Klotho's renal expression is invariably reduced in CKD. However, the mechanisms responsible for this silencing have not yet been fully elucidated. Studies point out to an epigenetic control, in particular histone deacetylation and hypermethylation in the promoter region of DNA. Changes in the methylation pattern may be triggered by the change in expression/activity of TET proteins, which are involved in the active process of DNA demethylation. Notably, these proteins promote the hydroxymethylation of methylated cytosines, especially in highly differentiated cells such as podocytes. Thus, the general objective of this study is to investigate whether there is a dysregulation in the expression and function of TET proteins and whether there is a reflex in the epigenetic control of Klotho and consequently in its target pathways implicated in renal injury observed in FSGS. For this, an animal model of FSGS (BALB/c mice with adriamycin-induced nephropathy) will be used and total renal tissue and podocytes isolated from these animals will be studied. In addition, the possible therapeutic effects of ascorbic acid (inducer of TET protein expression/activity) and 2'-deoxy-5-azacytidine (DNA methyltransferase inhibitor) will be investigated. With these results we intend to advance the understanding about the contribution of epigenetic control of TETs and Klotho proteins in the pathogenesis of podocyte damage in FSGS and thus point out a possible new strategy for its treatment. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PEREIRA, BEATRIZ MARIA VELOSO; DE PONTE, MARIANA CHARLEAUX; LUZ, ANA PAULA MALAVOLTA; THIEME, KARINA. DNA methylation enzymes in the kidneys of male and female BTBR ob/ob mice. FRONTIERS IN ENDOCRINOLOGY, v. 14, p. 10-pg., 2023-04-05. (19/10583-0, 18/00573-4, 21/12782-0, 20/15557-4)

THIEME, KARINA; VELOSO PEREIRA, BEATRIZ MARIA; DA SILVA, KAROLLINE S.; FABRE, NELLY T.; CATANOZI, SERGIO; PASSARELLI, MARISA; CORREA-GIANNELLA, MARIA LUCIA. Chronic advanced-glycation end products treatment induces TXNIP expression and epigenetic changes in glomerular podocytes in vivo and in vitro. Life Sciences, v. 270, APR 1 2021. (18/00573-4, 19/10583-0, 16/15603-0, 16/04591-1, 12/04831-1, 12/18724-2, 13/00713-7, 14/17251-9)

PEREIRA, BEATRIZ MARIA VELOSO; KATAKIA, YASH T.; MAJUMDER, SYAMANTAK; THIEME, KARINA. Unraveling the epigenetic landscape of glomerular cells in kidney disease. JOURNAL OF MOLECULAR MEDICINE-JMM, v. 99, n. 6, MAR 2021. (19/10583-0, 18/00573-4)

PANDYA THAKKAR, NIYATI; PEREIRA, BEATRIZ MARIA VELOSO; KATAKIA, YASH T.; RAMAKRISHNAN, SHYAM KUMAR; THAKAR, SUMUKH; SAKHUJA, ASHIMA; RAJEEV, GAYATHRY; SOORYA, S.; THIEME, KARINA; MAJUMDER, SYAMANTAK. Elevated H3K4me3 Through MLL2-WDR82 upon Hyperglycemia Causes Jagged Ligand Dependent Notch Activation to Interplay with Differentiation State of Endothelial Cells. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, v. 10, p. 16-pg., 2022-03-22. (18/00573-4, 19/10583-0)