TNF-alpha and podocyte dysfunction in diabetic kidney disease

• Grant number: 21/12782-0
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: August 01, 2022
• Status: Discontinued
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Karina Thieme
• Grantee: Mariana Charleaux de Ponte
• 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): 24/09605-7 - ORGANOIDS AS A MODEL FOR STUDYING COMPLEMENT-MEDIATED KIDNEY DISEASES, BE.EP.PD

Abstract

Diabetic kidney disease (DKD) is a complication that develops in approximately 40% of patients with type 2 diabetes mellitus (T2DM) and represents one of the main causes of progression to chronic kidney disease (CKD). It is known that inflammation, both systemic and local, plays an important role in the development of DKD. Macrophages are among the main types of immune cells present in kidneys of patients with DM2 and are sources of pro-inflammatory cytokines production, such as tumor necrosis factor alpha (TNF-±). The blockade of TNF-± results in decreased albumin excretion in animals and patients with DKD, which indicates the participation of this cytokine in glomerular injury. Furthermore, in other tissues, the role of TNF-± as an epigenetic modulator has been observed, a condition that can lead to podocyte (cells that make up the glomerular filtration barrier) dysfunction. Thus, the main objective of this proposal is to evaluate the participation of glomerular inflammation, mediated by TNF-±, in the epigenetic mechanisms involved in the injury and dedifferentiation of podocytes in an obesity-related DKD model. The first approach, in vivo, the gene and protein expression of the TNF-± pathway and the cell dedifferentiation pathways in the renal tissue of BTBR ob/ob male and female obese and T2DM mice will be investigated. In a second approach, in vitro, the participation of TNF-±, in a non-diabetic and diabetic context, in the expression of epigenetic markers associated with injury and dedifferentiation in mouse lineage podocytes will be evaluated. With the current proposal, we intend to explain the ways in which TNF-± contributes to podocyte injury and, consequently, to the progression of DKD in a model of obesity and T2DM.

Scientific publications

(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)