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Role of the Klotho/FGF23 axis in the development of Type 3 Cardiorenal Syndrome induced by ischemic renal injury

Grant number: 18/03089-6
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): July 01, 2018
Effective date (End): April 30, 2023
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Marcela Sorelli Carneiro Ramos
Grantee:Carolina Victória da Cruz Junho
Home Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil
Associated scholarship(s):18/19204-9 - Efects of the silencing and super-expressing of Klotho gene in cardiac function through hypertrophy induced by cardiorenal syndrome, BE.EP.DD


In diseases that generate an inflammatory situation, such as Cardiorenal Syndrome, different clinical conditions promote cardiac and renal dysfunction. It has five different types and the first two (types 1 and 2) are associated anormalities in cardiac function that cause injury or renal dysfunction; type 3 and 4 are characterized by renal insults that subject the heart to dysfunctions; the ype 5 is characterized by systemic diseases that induce both cardiac and renal dysfunctions. It is known that renal insufficiency (IR) and Chronic Kidney Disease (CKD) are characterized by a systemic inflammatory picture that can reach the heart tissue leading to a series of alterations. Among these changes, we can mention the modulation in Klotho levels, a gene that is negatively regulated by fibroblast growth factor 23 (FGF23). Studies indicate that the Klotho/FGF23 axis is closely associated with the Cardiorenal Syndrome since systemic inflammation causes the acetylation of histones in the Klotho gene, reducing its expression. This reduction increases FGF23, which in large numbers is detrimental to cardiac function, since it increases the risk of Atherosclerosis due to the alteration of phosphate and intracellular calcium homeostasis. Since the cardiorenal syndrome is a clinical picture of a high incidence and relevance in the world population, a detailed and systematic study of the Klotho/FGF axis23 and its subsequent action in the face of the cardiovascular alterations induced by renal injury is necessary. Considering the above, the objective of this study is to evaluate the participation of this axis in Cardiac Hypertrophy induced by renal ischemia, mainly evaluating intracellular calcium and EC (Excitation-Contraction) and ET (Excitation Transcription) coupling in the heart. To do so, the renal ischemia and reperfusion model in knockout mice for Klotho and superexpressed Klotho will be used, by occlusion of the left renal pedicle for 60 minutes, followed by reperfusion in the short term (for 5, 8 and 15 days) and long term (from 6 to 12 weeks). (AU)