A study conducted at the Center for Research on Redox Processes in Biomedicine (Redoxoma) at the University of São Paulo (USP) helps to understand how an inherited condition that affects the kidneys – autosomal dominant polycystic kidney disease (ADPKD) – can lead to the development of dysfunction heart disease, now considered the main cause of death in these patients.
In an article published in the journal Biochimica et Biophysica Acta (BBA) – Molecular Basis of Diseasescientists first described the metabolic reprogramming that occurs in the heart and the mitochondrial abnormalities (which affect the cell organelle responsible for energy production) that arise in the context of ADPKD.
Although the study was done in an animal model, several of the observed changes could potentially be applicable to human disease.
As the authors explain, ADPKD is a systemic disease that leads to the formation of multiple and bilateral renal cysts and to the progressive loss of renal function, in addition to presenting extrarenal manifestations, such as cardiovascular changes.
According to estimates, the disease affects one in every thousand people. In the vast majority of cases, it is caused by mutations in the Pkd1 gene, which encodes the polycystin-1 protein, or in the Pkd2 gene, which encodes polycystin-2.
In the last decades, many studies were directed to the understanding of the molecular mechanisms involved in the formation of renal cysts in the context of ADPKD. And metabolic defects have gained prominence in recent years. However, the molecular mechanisms involved in cardiac dysfunction associated with ADPKD are still unknown.
“This pioneering work proposes that metabolic alterations are involved in cardiac dysfunction associated with functional polycystin-1 deficiency, revealing common and different aspects from those described for cystic kidneys from animal models in the gene orthologous to Pkd1 [o gene correspondente no modelo animal]. It is an initial study, which opens the possibility of proposing therapeutic interventions. In the past, people with this disease died of kidney failure, but now, with dialysis and kidney transplantation, most deaths are due to cardiovascular changes”, says Andressa Godoy Amaral, first author of the article.
Amaral carried out the research during his doctorate, under the supervision of Professor Luiz Fernando Onuchic, responsible for the Cellular, Genetic and Molecular Nephrology Laboratory at the USP School of Medicine.
The work had the collaboration of researchers Alicia Kowaltowski and Sayuri Miyamoto, both from the Institute of Chemistry at USP and from Redoxoma, one (CEPID Center for Research, Innovation and Dissemination) of Fapesp Metabolomics studies were carried out at the LNBio (National Biosciences Laboratory), in Campinas.
Miyamoto’s group was responsible for the lipidomic analysis (of the lipid profile) of cardiac tissue. The data obtained, according to the researcher, served to demonstrate the extensive lipid remodeling that occurs in the heart. They also served as a basis for generating hypotheses about dysregulated lipid metabolism pathways.
metabolic reprogramming
The heart is a metabolically very active organ, in which mitochondria account for 25% to 30% of the volume of cardiomyocytes, the cardiac muscle cells, explains Amaral. And most of the energy used by the heart comes from the oxidation of fatty acids, meaning the heart mainly uses fat for energy.
But this only happens after birth, when the availability of oxygen is greater. The fetal heart predominantly uses glucose as a substrate for the production of ATP (adenosine triphosphate, the molecule used as fuel by cells).
“A common characteristic of several cardiac dysfunctions is this ‘dedifferentiation’ to the fetal phenotype. In other words, the heart returns to prefer alternative substrates instead of fatty acid. And we saw exactly that in this work, a metabolic reprogramming of the heart”, he says. Amaral.
To analyze the impact of polycystin-1 on cardiac metabolism, the researchers used mice named Pkd1V/V, which are unable to cleave (break down) this protein at the GPS site and have intensely cystic kidneys and early cardiac dysfunction. “This protein is large and complex and depends on a cleavage at the GPS site to mature and migrate to the places where it will act”, explained Amaral.
The study showed that Pkd1V/V hearts had lower levels of glucose and amino acids, as well as higher levels of lipids than organs from control animals.
This observation suggested decreased beta-oxidation of fatty acids in Pkd1V/V hearts, which was confirmed by the lower oxygen consumption by mitochondria in the presence of fatty acid.
In addition, they had a higher density of mitochondria of reduced size and increased apoptosis (programmed cell death) and inflammation. However, the hearts of these animals were not hypertrophied.
Tissues and mitochondria from the heart of animals with 15 days of life were analyzed, the age at which Pkd1V/V mice present both cardiac dysfunction and renal cysts.
Complementarily, some analyzes were performed on cardiomyocytes isolated from neonates (0 to 3 days old), at which age there is no presence of renal cysts, to assess cardiac alterations that are certainly independent of the renal phenotype. Comparisons were made between Pkd1V/V animals and wild-type controls and confirmed metabolic rearrangement.
According to the authors of the article, this study links polycystin-1 cleavage to heart development and maintenance of cardiac metabolic homeostasis. It can be considered, therefore, a conceptual landmark in the elucidation of the pathogenesis of cardiac dysfunction associated with the functional deficiency of this protein.
* With information from the Redoxoma Communications Office.
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