Rabphilin silencing causes dilated cardiomyopathy in a Drosophila model of nephrocyte damage

Abstract

Heart failure (HF) and the development of chronic kidney disease (CKD) have a direct association. Both can be cause and consequence of the other. Many factors are known, such as diabetes or hypertension, which can lead to the appearance and/or development of these two conditions. However, it is suspected that other factors, namely genetic ones, may explain the differences in the manifestation and progression of HF and CKD among patients. One candidate factor is Rph, a gene expressed in the nervous and excretory system in mammals and Drosophila, encoding a Rab small GTPase family effector protein implicated in vesicular trafficking. We found that Rph is expressed in the Drosophila heart, and the silencing of Rph gene expression in this organ had a strong impact in the organization of fibers and functional cardiac parameters. Specifically, we observed a significant increase in diastolic and systolic diameters of the heart tube, which is a phenotype that resembles dilated cardiomyopathy in humans. Importantly, we also show that silencing of Rabphilin (Rph) expression exclusively in the pericardial nephrocytes, which are part of the flies' excretory system, brings about a non-cell-autonomous effect on the Drosophila cardiac system. In summary, in this work, we demonstrate the importance of Rph in the fly cardiac system and how silencing Rph expression in nephrocytes affects the Drosophila cardiac system.

Drosophila Heart as a Model for Cardiac Development and Diseases

“…The Drosophila model has helped to identify novel genes and pathways involved in arrhythmias [47], atrial fibrillation [80], and channelopathies [81]. It has also been applied to modeling cardiac aging [51], and cardiomyopathies including dilated [82][83][84][85][86][87], hypertrophic [88][89][90], and restrictive cardiomyopathy [82,91,92], in which heart failure could occur [43]. Finally, the developed Drosophila models of muscular diseases with cardiac symptoms such as DM1 have been instrumental in dissecting the gene deregulations underlying heart defects and in identifying new therapeutic strategies.…”

Diurnal expression of Dgat2 induced by time‐restricted feeding maintains cardiac health in the Drosophila model of circadian disruption

“…Hearts from 3‐ and 7‐week‐old LD and LL male flies under ALF and TRF were collected and fixed at ZT4–8. Myofibril organization was assessed at the same regions where cardiac performance measurements were performed (Figure 2a) and then analyzed using Voronoi's diagram (Selma‐Soriano et al., 2021) (Supplementary 2a, b). In a young and healthy fly heart, myofibrils are paralleled and densely packed (Figure 2a).…”

zDHHC9 Regulates Cardiomyocyte Rab3a Activity and Atrial Natriuretic Peptide Secretion Through Palmitoylation of Rab3gap1

“…Rab3a has been extensively studied in neurotransmitter release and regulated exocytosis in neurons and chromaffin cells. 37,39 58 However, despite expression of Rab3 and its regulators and effectors in the heart, 33 , 34 , 38 , 79 its roles in cardiomyocyte biology remain elusive. Established functions of Rab proteins in cardiomyocytes are largely limited to regulation of ion-channel trafficking 32 and mitophagy.…”