Cardiac alterations induced by renal inflammation models: participation of the Klotho/FGF-23 axis

Abstract

Cardiorenal Syndrome is characterized by the presence of a systemic inflammatory condition where different clinical conditions promote cardiac and renal dysfunction. It has five different types where the first two (types 1 and 2) are associated with abnormalities in cardiac function that cause injury or renal dysfunction; the type 3 and 4 that are characterized by renal insults that subject the heart to dysfunctions; the latter type 5 is characterized by systemic diseases that induce both cardiac and renal dysfunction. It is known that renal insufficiency (IR) and chronic kidney disease (CKD) are characterized by a systemic inflammatory picture that can reach cardiac 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 have pointed out that the Klotho / FGF23 axis is closely associated with cardiorenal syndrome since systemic inflammation causes the acetylation of histones in the Klotho gene, reducing its expression. Another type of renal injury, associated with elevated levels of uremic compounds, such as Indoxyl Sulfate (IS) for example, common in dialytic patients, plays a hypertrophic role in cardiomyocyte cultures through the activation of MAPKs (Mitogen-Activated Protein Kinases) and NFºB (Nuclear Kappa Beta Factor), indicating that IS may play an important role in the development of cardiac hypertrophy under uremic conditions. Uremic solutes, such as IS, may also inhibit expression of the Klotho gene in renal tubular epithelial cells by affecting hypermethylation of cytosine phosphate-guanine and increased hypermethylation of DNA. In view of the above, this study aims to evaluate the effect of soluble Klotho supplementation on two different models of renal injury: I) renal injury due to ischemia / reperfusion, already established and consolidated model in our laboratory and II) treatment with IS uremic compound. The present study aims to evaluate cardiac alterations through functional assays, morphological and molecular analyzes of cardiac tissue, after treatment with soluble Klotho. (AU)