Modelling Renal Development and Disease in Drosophila

Abstract

The discovery that the cells involved in haemolymph ultrafiltration in the fruit fly Drosophila melanogaster (nephrocytes) have filtration diaphragms molecularly and functionally related to vertebrate slit diaphragms, present in kidney podocytes, led to the suggestion that nephrocytes could be used to study slit diaphragm assembly and maintenance. Recent findings have strengthened this hypothesis after demonstrating that the similarities between both diaphragms extend to the mechanisms involved in the regulation of their stability. As most nephrotic syndromes somehow affect the stability of the slit diaphragm, these observations open the possibility of using Drosophila as a powerful model organism to study renal disease.

Key Concepts

  • Most congenital and acquired nephrotic syndromes are associated to dysfunction of the glomerular filtration barrier and affect the podocyte slit diaphragm(SD).
  • Drosophila nephrocytes, the cells that filtrate the haemolymph, have filtration diaphragms resembling SDs.
  • Drosophila and vertebrate SDs are made up of orthologue proteins.
  • The regulatory mechanisms controlling SD dynamics are conserved between humans and flies.
  • Drosophila nephrocytes can be used to model renal diseases that affect the SD.
  • The powerful genetics of Drosophila converts the fly in a suitable animal model for the development of future genetic and drug screens designed to identify novel therapeutic targets for the treatment of renal disease.

Keywords: Drosophila melanogaster ; nephrocyte; slit diaphragm; podocyte; renal disease

Figure 1. Schematic representations of excretory organs in humans and in Drosophila. (a) Illustration of a nephron showing the glomerulus, the site of ultrafiltration, and the proximal tubule, the loop of Henle and the distal tubule where the processes of reabsorption and secretion take place. The afferent and efferent arteriole and the collecting duct are also indicated. (b) Scheme showing the location of the major excretory organs of a Drosophila larva, the pericardial and garland nephrocytes that filter the haemolymph and the malpighian tubules, the organs specialised in reabsorption, secretion and excretion.
Figure 2. The glomerular filtration barrier. (Left) Diagrams showing the evolution of cell junctions during podocyte development. Note the displacement of occludens junctions (green) from the apical region of the podocytes towards more lateral positions, to end up joining adjacent podocytes at their basal surface where slit diaphragm will appear. (Middle) Scheme of a glomerulus formed by a tuft of capillaries, the podocytes that enwrap them, shown in detail in the inset, and the Bowman capsule. (Right) Schematic representation of the glomerular filtration barrier composed by the fenestrated endothelium, the glomerular basement membrane (GBM) and the podocyte slit diaphragm. The main components of the slit diaphragm multi‐protein complex are indicated.
Figure 3. Drosophila nephrocyte. (a) Transmission electron micrograph of a larval nephrocyte illustrating the presence of two nuclei (N), a prominent developed ER, different types of vesicles, many mitochondria and the cortical region formed by the labyrinthine channels, sealed by slit diaphragms. (b) Diagram displaying the main organelles present in nephrocytes. (c) Scheme of a labyrinthine channel, showing the components of the nephrocyte filtration barrier, the basement membrane (BM) and the filtration diaphragm, whose main constituents are indicated.
Figure 4. Morphological transformations of podocytes and nephrocytes in response to injury. (a) Podocyte foot process effacement; the loss of slit diaphragms causes the regression of the podocyte interdigitating extensions. (b) In Drosophila, loss of filtration diaphragms induces nephrocyte agglutination.
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Further Reading

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Carrasco‐Rando, Marta, Atienza‐Manuel, Alexandra, Tutor, Antonio S, and Ruiz‐Gómez, Mar(Apr 2015) Modelling Renal Development and Disease in Drosophila . In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025981]