Modelling Renal Development and Disease in Drosophila


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.


Aggarwal SK and King RC (1967) The ultrastructure of the wreath cells of Drosophila melanogaster larvae. Protoplasma 63: 343–352.

Barletta GM , Kovari IA , Verma RK , et al. (2003) Nephrin and Neph1 co‐localize at the podocyte foot process intercellular junction and form cis hetero‐oligomers. Journal of Biological Chemistry 278: 19266–71.

Benzing T (2004) Signaling at the slit diaphragm. Journal of the American Society of Nephrology 15: 1382–91.

Boute N , Gribouval O , Roselli S , et al. (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid‐resistant nephrotic syndrome. Nature Genetics 24: 349–54.

Ciani L , Patel A , Allen ND , et al. (2003) Mice lacking the giant protocadherin mFAT1 exhibit renal slit junction abnormalities and a partially penetrant cyclopia and anophthalmia phenotype. Molecular and Cellular Biology 23: 3575–82.

Crossley AC (1972) The ultrastructure and function of pericardial cells and other nephrocytes in an insect: Calliphora erythrocephala. Tissue and Cell 4: 529–60.

Denholm B (2013) Shaping up for action: the path to physiological maturation in the renal tubules of Drosophila . Organogenesis 9: 40–54.

Denholm B and Skaer H (2009) Bringing together components of the fly renal system. Current Opinion in Genetics and Development 19: 526–32.

Donoviel DB , Freed DD , Vogel H , et al. (2001) Proteinuria and perinatal lethality in mice lacking NEPH1, a novel protein with homology to NEPHRIN. Molecular and Cellular Biology 21: 4829–36.

Doublier S , Salvidio G , Lupia E , et al. (2003) Nephrin expression is reduced in human diabetic nephropathy: evidence for a distinct role for glycated albumin and angiotensin II. Diabetes 52: 1023–30.

Faul C , Asanuma K , Yanagida‐Asanuma E , et al. (2007) Actin up: regulation of podocyte structure and function by components of the actin cytoskeleton. Trends in Cell Biology 17: 428–37.

Freeman AA , Syed S and Sanyal S (2013) Modeling the genetic basis for human sleep disorders in Drosophila . Communicative & Integrative Biology 6: e22733.

Fukusumi Y , Miyauchi N , Hashimoto T , et al. (2014) Therapeutic target for nephrotic syndrome: Identification of novel slit diaphragm associated molecules. World Journal of Nephrology 3: 77–84.

Gerke P , Huber TB , Sellin L , et al. (2003) Homodimerization and heterodimerization of the glomerular podocyte proteins nephrin and NEPH1. Journal of the American Society of Nephrology 14: 918–26.

Gonzalez C (2013) Drosophila melanogaster: a model and a tool to investigate malignancy and identify new therapeutics. Nature Reviews. Cancer 13: 172–83.

Grahammer F , Schell C and Huber TB (2013) Molecular understanding of the slit diaphragm. Pediatric Nephrology 28: 1957–62.

Harita Y , Kurihara H , Kosako H , et al. (2008) Neph1, a component of the kidney slit diaphragm, is tyrosine‐phosphorylated by the Src family tyrosine kinase and modulates intracellular signaling by binding to Grb2. Journal of Biological Chemistry 283: 9177–86.

Harita Y , Kurihara H , Kosako H , et al. (2009) Phosphorylation of nephrin triggers Ca2+ signaling by recruitment and activation of phospholipase C‐{gamma}1. Journal of Biological Chemistry 284: 8951–62.

Hattori S , Kanda S and Harita Y (2011) Tyrosine kinase signaling in kidney glomerular podocytes. Journal of Signal Transduction 2011: 317852.

Helmstadter M , Luthy K , Godel M , et al. (2012) Functional study of mammalian Neph proteins in Drosophila melanogaster . PLoS One 7: e40300.

Inoue T , Yaoita E , Kurihara H , et al. (2001) FAT is a component of glomerular slit diaphragms. Kidney International 59: 1003–12.

Jones N , Blasutig IM , Eremina V , et al. (2006) Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 440: 818–23.

Kelley VE and Cavallo T (1976) An ultrastructural study of the glomerular slit diaphragm in New Zealand black/white mice. Laboratory Investigation 35: 213–20.

Kestila M , Lenkkeri U , Mannikko M , et al. (1998) Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Molecular Cell 1: 575–82.

Kriz W , Shirato I , Nagata M , et al. (2013) The podocyte's response to stress: the enigma of foot process effacement. American Journal of Physiology. Renal Physiology 304: F333–47.

Luimula P , Sandstrom N , Novikov D , et al. (2002) Podocyte‐associated molecules in puromycin aminonucleoside nephrosis of the rat. Laboratory Investigation 82: 713–8.

Mills RP and King RC (1965) The pericardial cells of Drosophila melanogaster . Quarterly Journal of Microscopical Science 106: 261–8.

Nakhoul F , Ramadan R , Khankin E , et al. (2005) Glomerular abundance of nephrin and podocin in experimental nephrotic syndrome: different effects of antiproteinuric therapies. American Journal of Physiology. Renal Physiology 289: F880–90.

Pandey UB and Nichols CD (2011) Human disease models in Drosophila melanogaster and the role of the fly in therapeutic drug discovery. Pharmacological Reviews 63: 411–36.

Park J , Al‐Ramahi I , Tan Q , et al. (2013) RAS‐MAPK‐MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498: 325–31.

Patrakka J and Tryggvason K (2009) New insights into the role of podocytes in proteinuria. Nature Reviews. Nephrology 5: 463–8.

Rajan A and Perrimon N (2013) Of flies and men: insights on organismal metabolism from fruit flies. BMC Biology 11: 38.

Reeves W , Caulfield JP and Farquhar MG (1978) Differentiation of epithelial foot processes and filtration slits: sequential appearance of occluding junctions, epithelial polyanion, and slit membranes in developing glomeruli. Laboratory Investigation 39: 90–100.

Rizki TM (1978) The circulatory system and associated cells and tissues. In: Ashburner M and Wright TRF , (eds). The Genetics and Biology of Drosophila , pp. 397–452. London: Academic Press.

Rodewald R and Karnovsky MJ (1974) Porous substructure of the glomerular slit diaphragm in the rat and mouse. Journal of Cell Biology 60: 423–33.

Rugendorff A , Younossi‐Hartenstein A and Hartenstein V (1994) Embryonic origin and differentiation of the Drosophila heart. Roux's Archives of Developmental Biology 203: 266–80.

Ryan GB , Rodewald R and Karnovsky MJ (1975) An ultrastructural study of the glomerular slit diaphragm in aminonucleoside nephrosis. Laboratory Investigation 33: 461–8.

Schwarz K , Simons M , Reiser J , et al. (2001) Podocin, a raft‐associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. Journal of Clinical Investigation 108: 1621–9.

Shih NY , Li J , Karpitskii V , et al. (1999) Congenital nephrotic syndrome in mice lacking CD2‐associated protein. Science 286: 312–5.

Shih NY , Li J , Cotran R , et al. (2001) CD2AP localizes to the slit diaphragm and binds to nephrin via a novel C‐terminal domain. American Journal of Pathology 159: 2303–8.

Tryggvason K , Pikkarainen T and Patrakka J (2006a) Nck links nephrin to actin in kidney podocytes. Cell 125: 221–4.

Tutor AS , Prieto‐Sanchez S and Ruiz‐Gomez M (2014) Src64B phosphorylates dumbfounded and regulates slit diaphragm dynamics: Drosophila as a model to study nephropathies. Development 141: 367–76.

de Velasco B , Mandal L , Mkrtchyan M , et al. (2006) Subdivision and developmental fate of the head mesoderm in Drosophila melanogaster . Development Genes and Evolution 216: 39–51.

Wartiovaara J , Ofverstedt LG , Khoshnoodi J , et al. (2004) Nephrin strands contribute to a porous slit diaphragm scaffold as revealed by electron tomography. Journal of Clinical Investigation 114: 1475–83.

Weavers H , Prieto‐Sanchez S , Grawe F , et al. (2009) The insect nephrocyte is a podocyte‐like cell with a filtration slit diaphragm. Nature 457: 322–6.

Yu CC , Yen TS , Lowell CA , et al. (2001) Lupus‐like kidney disease in mice deficient in the Src family tyrosine kinases Lyn and Fyn. Current Biology 11: 34–8.

Zhang Y , Yoshida Y , Nameta M , et al. (2010) Glomerular proteins related to slit diaphragm and matrix adhesion in the foot processes are highly tyrosine phosphorylated in the normal rat kidney. Nephrology, Dialysis, Transplantation 25: 1785–95.

Zhang F , Zhao Y , Chao Y , et al. (2013) Cubilin and amnionless mediate protein reabsorption in Drosophila nephrocytes. Journal of the American Society of Nephrology 24: 209–16.

Zhuang S , Shao H , Guo F , et al. (2009) Sns and Kirre, the Drosophila orthologs of Nephrin and Neph1, direct adhesion, fusion and formation of a slit diaphragm‐like structure in insect nephrocytes. Development 136: 2335–44.

Further Reading

Dow JA and Romero MF (2010) Drosophila provides rapid modeling of renal development, function, and disease. American Journal of Physiology. Renal Physiology 299: F1237–44.

Garg P , Verma R and Holzman LB (2007) Slit diaphragm junctional complex and regulation of the cytoskeleton. Nephron. Experimental Nephrology 106: e67–72.

Haraldsson B , Nystrom J and Deen WM (2008) Properties of the glomerular barrier and mechanisms of proteinuria. Physiological Reviews 88: 451–87.

Na J and Cagan R (2013) The Drosophila nephrocyte: back on stage. Journal of the American Society of Nephrology 24: 161–3.

Simons M and Huber TB (2009) Flying podocytes. Kidney International 75: 455–7.

Tryggvason K , Patrakka J and Wartiovaara J (2006b) Hereditary proteinuria syndromes and mechanisms of proteinuria. New England Journal of Medicine 354: 1387–401.

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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. [doi: 10.1002/9780470015902.a0025981]