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

Estela Selma-Soriano,Juan Antonio Navarro,Josep Redón,Rubén Artero,Carlos Casillas-Serra,Beatriz Llamusi

doi:10.1038/s41598-021-94710-7

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.

Highlights

Heart failure (HF) and the development of chronic kidney disease (CKD) have a direct association
We observed Rph expression in nephrocytes[9], and in this study, we report that Rph is expressed in the Drosophila heart tube with a punctate pattern in the cytoplasm of cardiomyocytes (Fig. 1 and Supplementary Figure 1A, A′, C, C′, E and E′)
To demonstrate the specificity of the antibody, the same assay was performed in flies with combined Rph RNAi, with two different lines of Rph RNAi constructs, in cardiomyocytes and nephrocytes (Hand-Gal[4] UAS-GFP > UAS-IR-Rabphilin), and an important reduction of Rph expression was observed both in the cardiac tube and in nephrocytes (Fig. 1A–B′, G, Supplementary Figure 1A–B′, G, and Fig. 2A–B′, G)

Summary

Introduction

Heart failure (HF) and the development of chronic kidney disease (CKD) have a direct association. Association between heart failure (HF) and chronic kidney disease (CKD) is recognized in multiple epidemiological and clinical studies Both can be cause and consequence of each o ther[1] multiple factors are known to contribute to developing both HF and CKD, such as diabetes and h ypertension[1,2], there are still unknown factors that could explain differences in the progression of HF and/or CKD among patients. Both cardiomyocytes and podocytes, specialized cells of the heart and kidney, respectively, play a key role in maintaining these organs’ functional integrity. Even though Rab proteins and the proteins that interact with them are expressed in cardiomyocytes and are related to heart problems that lead to heart failure[3], the functions of the Rab GTPases and their effectors, such as Rph-3A, in the heart system are poorly understood

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Results

Conclusion