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Drosophila melanogaster: a simple genetic model of kidney structure, function and disease

Nature Reviews Nephrology volume 18, pages 417–434 (2022)Cite this article

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A Publisher Correction to this article was published on 10 November 2023

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Abstract

Although the genetic basis of many kidney diseases is being rapidly elucidated, their experimental study remains problematic owing to the lack of suitable models. The fruitfly Drosophila melanogaster provides a rapid, ethical and cost-effective model system of the kidney. The unique advantages of D. melanogaster include ease and low cost of maintenance, comprehensive availability of genetic mutants and powerful transgenic technologies, and less onerous regulation, as compared with mammalian systems. Renal and excretory functions in D. melanogaster reside in three main tissues — the transporting renal (Malpighian) tubules, the reabsorptive hindgut and the endocytic nephrocytes. Tubules contain multiple cell types and regions and generate a primary urine by transcellular transport rather than filtration, which is then subjected to selective reabsorption in the hindgut. By contrast, the nephrocytes are specialized for uptake of macromolecules and equipped with a filtering slit diaphragm resembling that of podocytes. Many genes with key roles in the human kidney have D. melanogaster orthologues that are enriched and functionally relevant in fly renal tissues. This similarity has allowed investigations of epithelial transport, kidney stone formation and podocyte and proximal tubule function. Furthermore, a range of unique quantitative phenotypes are available to measure function in both wild type and disease-modelling flies.

Key points

  • The fruitfly Drosophila melanogaster has proved to be a valuable experimental model for the study of human biology and has major advantages, including low costs and a broad variety of established genetic tools and interventions.

  • The fly renal tubule — Malpighian tubule — secretes fluid faster (on a per-cell volume basis) than any other tissue, and is ideal for investigating secretory or transport phenotypes, such as nephrolithiasis.

  • Nephrocytes express many proteins that are also found in the slit diaphragm of podocytes and perform a specialized role by sequestering and breaking down filtered molecules such as proteins; the ability of nephrocytes to reabsorb filtered molecules is analogous to the reabsorptive capacity of the proximal tubule.

  • A wide range of models of kidney diseases have been developed in D. melanogaster.

  • D. melanogaster uniquely represents an organism with a recognizable renal system that is compatible with large-scale chemical or genetic screens.

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Fig. 1: The D. melanogaster excretory system.
Fig. 2: Key genes and functions of the D. melanogaster renal tubule.
Fig. 3: Experimental approaches to the D. melanogaster renal system.
Fig. 4: Use of D. melanogaster to identify new treatments for nephrolithiasis.
Fig. 5: The mammalian kidney filtration apparatus and the D. melanogaster nephrocyte.

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Acknowledgements

J.A.T.D. and M.F.R. were supported by grants from the US National Institutes of Health (NIH) R01-DK092408, U54-DK100227. M.F.R. was also supported by the Mayo Foundation, the Oxalosis & Hyperoxaluria Foundation (OHF) and NIH grants P30-DK090728 and R25-DK101405. J.A.T.D. was further supported by grants from the UK BBSRC, the European Commission Horizon 2020, and Marie Slodowska-Curie Actions. The authors thank Shireen Davies, Alan Jardine, Peter Harris, John Lieske, Steve Ekker, Nicholas LaRusso and Carli Sussman for critical reading of the manuscript before submission.

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Authors and Affiliations

  1. Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Julian A. T. Dow

  2. INSERM UMR1163, Laboratory of Epithelial Biology and Disease, Imagine Institute, Université de Paris, Hôpital Necker-Enfants Malades, Paris, France

    Matias Simons

  3. Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany

    Matias Simons

  4. Department of Physiology and Biomedical Engineering, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine and Science, Rochester, MN, USA

    Michael F. Romero

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All authors researched data for the article, made substantial contributions to discussions of the content, wrote the manuscript, and reviewed or edited the manuscript before submission.

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Correspondence to Julian A. T. Dow.

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Nature Reviews Nephrology thanks P. Hartley, A. Rodan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

FlyAtlas database: http://www.flyatlas.org/

FlyBase database: https://flybase.org/

NCBI Homologene database: https://www.ncbi.nlm.nih.gov/homologene

Supplementary information

Glossary

Specification

A stage in differentiation where a cell has sufficient information to differentiate in a particular way in a neutral environment; differs from the determination stage, at which a cell is committed to a specific fate.

Eversion

The out-pushing of a group of cells during the early stages of tubular epithelium formation.

Metanephric kidney

The fully differentiated mammalian kidney.

S-shaped bodies

An intermediate stage in the development of the mammalian nephron, in which proximal, medial and distal segments can already be identified.

Inward-rectifying K+ channels

K+-specific ion channels that display rectification (that is, K+ can enter the cell through the channels but cannot exit even under a favourable electrochemical gradient).

Euteleostomi

Phylogenetic group that includes nearly all living vertebrates.

Bilateria

A phylogenetic clade comprising animals with bilateral symmetry.

Morpholinos

Synthetic antisense nucleotides that interfere with complementary mRNAs (act in a similar manner to antisense RNAs or siRNAs); widely used in zebrafish studies.

Translocon

A complex of proteins that allow nascent peptides to cross a lipid bilayer, typically in the endoplasmic reticulum.

Peripheral membrane protein

A membrane-associated protein that is tethered to, but that does not cross, a plasma membrane.

Septate junction

Insect analogue of vertebrate tight junction with similarity in protein composition; these junctions appear as ladder-like septa in transmission electron microscopy.

Phase separation

The creation of two distinct phases from a homogeneous mixture.

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Dow, J.A.T., Simons, M. & Romero, M.F. Drosophila melanogaster: a simple genetic model of kidney structure, function and disease. Nat Rev Nephrol 18, 417–434 (2022). https://doi.org/10.1038/s41581-022-00561-4

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