Rabphilin involvement in filtration and molecular uptake in Drosophila nephrocytes suggests a similar role in human podocytes.

Selma-Soriano, Estela; Llamusi, Beatriz; Fernández-Costa, Juan Manuel; Ozimski, Lauren Louise; Artero, Rubén; Redón, Josep

Drosophila nephrocyte share functional, structural, and molecular similarities with human podocytes. It is known that podocytes express the Rabphilin 3A (RPH3A)-Rab3A complex, and its expression is altered in mouse and human proteinuric disease. Furthermore, we previously identified a polymorphism that suggested a role for RPH3A protein in the development of urinary albumin excretion. Since endocytosis and vesicle trafficking are fundamental pathways for nephrocytes, the objective here is to assess the role of the RPH3A ortholog in Drosophila, Rabphilin (Rph), in the structure and function of nephrocytes. We have confirmed that Rph is required for the endocytic pathway to function correctly in pericardial Drosophila nephrocytes. Knockdown of Rph reduces the expression of cubilin and stick and stones genes, which encode proteins that are involved in protein uptake and filtration. We also found that reduced Rph expression results in a disappearance of the labyrinthine channel structure and a reduction in the number of endosomes, which ultimately leads to changes in the number and volume of nephrocytes. Finally, we described that administration of retinoic acid to IR-Rph nephrocytes rescued some altered aspects as the filtration and molecular uptake as well as the maintenance of cell fate. According to our data, Rph is crucial for the nephrocyte's filtration and reabsorption and it is required for the maintenance of the nephrocyte's ultrastructure, integrity, and differentiation.