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Mechanisms for the key role of the LSD1 gene in cardiovascular and renal effects associated with a high salt diet

Grant number: 17/23647-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2018
Effective date (End): December 31, 2019
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Joel Claudio Heimann
Grantee:Mariana Moura Nascimento
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Hypertension (AH) is a well-established risk factor for the development of cardiovascular and renal diseases (CVR). The collaborative study group recently proposed a contributor to the aetiology of HA mediated by salt overload: Lysine Specific Demethylase-1 (LSD1). The candidate worked with this same group of studies and demonstrated that in mice, LSD1 deficiency accelerates the increase of blood pressure (BP) levels and the development of microalbuminuria when compared to wild type (WT) animals. Interestingly, in WT animals, salt restriction in the long-term diet prevented the cardiovascular effects observed in the group that received salt overload, but in the heterozygous and knockout animals for LSD1 (Het) this salt-poor diet was only able to slow the increase in (AP), but surprisingly did not prevent this effect. In addition, only WT animals receiving a salt-restricted diet had renal resistance index and glomerular volume with values considered normal. There was no difference in plasma aldosterone levels or plasma renin activity. This previous longitudinal study brings new and important concepts, but little is known about the mechanisms involved in the CVR alterations that this genotype brings. Thus, the objective of the current study is to elucidate the mechanisms involved in LSD1-deficient animals that are more susceptible (or may explain) the increased pressure and the development of microalbuminuria at earlier stages when compared to WT animals. Thus, the results of this research group in mice will give support and relevance to the use of the LSD1-deficient mouse model in a translational study, since the group in collaboration has important results in humans. Thus, the deficiency of LSD1 in mice (and potentially in the human genotype) acts as a functional biomarker for the development of microalbuminuria and the increase of the AP, independent of diet, and the onset of adulthood in these mice is a timely scenario to initiate measures prevent future damage to target organs. Specifically, litter of heterozygous and knockout mice were used for LSD1 and WT mice fed hypersodium (1.6% sodium), normosodic (0.26% sodium) or hyposodic (0.03% sodium) diets for 12 months and the methods to be performed are: histological analysis of renal tissue, quantification of ED-1, Angiotensin II and PCNA in renal tissue (immunohistochemistry), evaluation of AT1 and AT2 receptor activity, evaluation of gene expression and / or AT1 and MR receptors, as well as CD68, MCP1, klotho, CaSR, FGF23, SIRT1 and LSD1. (AU)