The role of DNA (hydroxy)methylation in podocytes dysfunction: epigenetic perspectives for the treatment of Chronic Kidney Disease

• Grant number: 18/00573-4
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: November 01, 2018
• End date: December 31, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Karina Thieme
• Grantee: Karina Thieme
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Andrew Advani ; Gerhard Malnic
• Associated scholarship(s): 21/12782-0 - TNF-alpha and podocyte dysfunction in diabetic kidney disease, BP.PD; 20/15557-4 - Analysis of Sirtuin 1 activation in restoring autophagy in podocytes, BP.IC; 19/10583-0 - Epigenetic regulation of TET and Klotho proteins in Glomerular Disease, BP.DR; 20/12114-4 - Investigation of epigenetic mechanisms involved in diabetic kidney disease, BP.MS

Abstract

Diabetic Kidney Disease (DKD) and Focal and Segmental Glomerulosclerosis (FSGS) are the main causes of Chronic Kidney Disease (CKD), a condition characterized by progressive loss of renal function and the presence of proteins in the urine. The loss of proteins is closely associated with the dysfunction of podocytes, highly specialized cells that make up the glomerular filtration barrier. The role of molecules with neproprotective properties that are secreted by the kidneys has gained attention, one of them "klotho". The interest is also due to its potential for modulation of functions that simultaneously control processes such as fibrosis, glucose metabolism, Epithelial-Mesenchymal Transition (EMT), oxidative stress, inflammation and autophagy. It is known that plasma and urinary levels of klotho are reduced in CKD, however the molecular mechanisms responsible for its silencing have not been elucidated. Some studies point out to an important epigenetic control of its expression. In fact, recent studies have shown that changes in the epigenome, in particular histone modifications and DNA methylation, confer alterations in the expression of innumerable genes involved in the renal injury process. Given the importance of TET protein activity in the DNA hydroxymethylation process and the consequent active demethylation, especially in highly differentiated cells such as podocytes, modifications in its expression trigger an imbalance of DNA methylation, with changes in gene expression. Thus, the general objective of this proposal is to explore the regulation of TET proteins expression in different CKD models and correlate the observed changes with the DNA hydroxymethylation function and the (epi)genetic dysregulation of klotho and target pathways involved in the kidney injury. Among the pathways, the Wnt/²-catenin pathway, which regulates EMT and cell dedifferentiation, and the autophagy pathway, essential for podocyte function, will be investigated. The proposal will be explored in vivo and in podocytes isolated from two different CKD models (DKD: STZ-induced model and FSGS: adriamycin-induced model), investigating the possible renoprotective effects ascorbic acid (a TET protein inducer) and 2'-deoxy-5-azacytidine (a DNA methyl transferase inhibitor). A second approach of the proposal will study, in vitro, in culture of human podocytes exposed to TGF-² and/or ascorbic acid or 2'-deoxy-5-azacytidine, the effects of dysregulation of TET proteins expression through its knockdown or over-expression on the development and progression of podocyte dysfunction. In addition, the expression and localization of TET and klotho proteins will be determined in human renal biopsies of control and CKD patients and correlated with their clinical data. The present project is translational, innovative and will allow the implementation of a new and original research in the department, focusing on the epigenetic mechanisms regulating renal injury. Finally, the results will pave new avenues and therapeutic strategies for the prevention of progression and treatment of CKD. (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)