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The hypoxia-inducible factor 1 alpha (HIF-1 alpha) and the metabolism of tubular epithelial cells and podocytes in the development and progression of experimental kidney disease

Grant number: 19/02893-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): April 01, 2019
Effective date (End): March 31, 2022
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Niels Olsen Saraiva Câmara
Grantee:Orestes Foresto Neto
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology, AP.TEM

Abstract

Renal disease and the consequent need for renal replacement therapy represent a serious global public health problem. The mechanisms involved in the progression of the chronic kidney disease (CKD) remain incompletely understood, which makes it difficult to develop effective strategies for its treatment. Recent studies suggest that the progression of CKD and the development of fibrosis are associated with changes in the glycolytic and oxidative metabolism of proximal tubular epithelial cells (PTECs) and podocytes. The energy homeostasis maintenance in cells involves a range of molecules, and the hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a key mediator in this process. Upon insufficient intracellular levels of oxygen, the HIF-1 alpha translocates to the nucleus of the cells, and acts as a transcriptional regulator for genes with promoters containing hypoxia-response element regions as genes related to glycolytic metabolism. However, disturbance of oxygen homeostasis and abnormal activity of HIF-1 alpha may contribute to the pathogenesis of diseases, including heart disease. Thus, a better understanding of the functions of HIF also in the activation of renal parenchymal cells and its participation in kidney diseases mediated by the immune system is necessary. In this project, we hypothesize that alterations in renal cell metabolism are modulated by HIF-1 alpha and are the common link between pro-inflammatory stimuli and the development of fibrosis. Using podocytes and PTECs isolated from wild type or HIF-1 alpha-deficient mice, we will analyze the role of HIF-1 alpha in the cellular energetic metabolism, focusing on glycolytic metabolism, in the presence of acute and chronic insults. Upon different stimuli, the activation of HIF-1 alpha, cellular metabolism and renal damage markers will be assessed in these cells by Seahorse, western blot, flow cytometry, gene expression and PCR array. Furthermore, we will verify if the same scenarios are present in vivo inducing renal fibrosis by adenine overload in the diet and focal segmental glomerulosclerosis by adriamycin injection in HIF-1 alpha knockout mice or in animals conditioned to not express HIF-1 alpha in podocytes or in PTECs. With this project, we aim to elucidate new mechanisms of kidney diseases and to reveal new therapeutic targets for the treatment of CKD.

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)
BRAGA, TARCIO TEODORO; FORESTO-NETO, ORESTES; SARAIVA CAMARA, NIELS OLSEN. The role of uric acid in inflammasome-mediated kidney injury. CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION, v. 29, n. 4, p. 423-431, JUL 2020. Web of Science Citations: 2.
ANDRADE-OLIVEIRA, VINICIUS; FORESTO-NETO, ORESTES; MIZUNO WATANABE, INGRID KAZUE; ZATZ, ROBERTO; SARAIVA CAMARA, NIELS OLSEN. Inflammation in Renal Diseases: New and Old Players. FRONTIERS IN PHARMACOLOGY, v. 10, OCT 8 2019. Web of Science Citations: 1.

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