Drosophila melanogaster as an emerging translational model of human nephrolithiasis

Abstract

Purpose: The limitations imposed by human clinical studies and mammalian models of nephrolithiasis have hampered the development of effective medical treatments and preventive measures for decades. The simple but elegant Drosophila melanogaster is emerging as a powerful translational model of human disease, including nephrolithiasis. It may provide important information essential to our understanding of stone formation. We present the current state of research using D. melanogaster as a model of human nephrolithiasis.

Materials and methods: We comprehensively reviewed the English language literature using PubMed®. When necessary, authoritative texts on relevant subtopics were consulted.

Results: The genetic composition, anatomical structure and physiological function of Drosophila malpighian tubules are remarkably similar to those of the human nephron. The direct effects of dietary manipulation, environmental alteration and genetic variation on stone formation can be observed and quantified in a matter of days. Several Drosophila models of human nephrolithiasis have been developed, including genetically linked and environmentally induced stones. A model of calcium oxalate stone formation is among the most recent fly models of human nephrolithiasis.

Conclusions: The ability to readily manipulate and quantify stone formation in D. melanogaster models of human nephrolithiasis presents the urological community with a unique opportunity to increase our understanding of this enigmatic disease.

Keywords: ATPase; CT; Drosophila melanogaster; UAS; XDH; adenosine triphosphatase; animal; computerized tomography; disease models; kidney; malpighian tubules; nephrolithiasis; upstream activation sequence; xanthine dehydrogenase.

Figure 1

Cartoon of D. melanogaster excretory tract. Two pairs of Malpighian tubules, one anterior and one posterior, are each connected to the gut by a common ureter.

Figure 2

Photomicrograph of two pair of Malpighian tubules dissected free from an adult D. melanogaster. Each pair coalesces into a common ureter.

Figure 3

The principal and stellate cell of the D. melanogaster Malpighian tubules.

Figure 4

Visual segregation of Drosophila melanogaster by sex is easily accomplished due to the longer, pointed abdomen of the female. The genome is comprised of three autosomal pairs and one sex pair.

Figure 5

Xanthine stones in the Malpighian tubules lumens of rosy mutants deficient in XDH.

Figure 6

Photomicrographs of (A) calcium oxalate crystal accumulation D. melanogaster fed diet supplemented with sodium oxalate (bottom), compared to control (top), (B) magnification of intraluminal calcium oxalate crystals, (C) magnified view of crystals, and (D–F) crystal formation in dissected Malpighian tubules in sodium oxalate bath. (Hirata, et al., 2012).

Figure 7

(A) MicroCT scan images of calcium oxalate crystal accumulation in three adult D. melanogaster fed a diet supplemented with sodium oxalate as compared to images of two controls, and (B) Surface renderings constructed from Micro-CT scan images (Hirata, et al., 2012). (Ox-Fed=oxalate fed flies, Ctl=control flies, MT=Malpighian tubules)