The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm

Abstract

The blood-filtering barrier in the glomerulus of the vertebrate kidney, where blood is ultrafiltered to form urine, is made up of modified epithelial cells called podocytes. The nephron — consisting of the glomerulus and renal tubule — is considered a characteristic adaptive feature of vertebrates. But 'nephron-like' features are found in the excretory systems of many invertebrates. Now Weavers et al. report that an insect filtration cell known as the nephrocyte shares striking similarity with the podocyte. Fly orthologues of the major constituents of the slit diaphragm of the kidney form a complex of interacting proteins resembling that found in vertebrates. The nephrocyte diaphragm is completely lost in flies mutant for nephrin or NEPH1 orthologues, similar to the phenotype of the human kidney disease congenital nephrotic syndrome (NPHS1). This establishes the insect nephrocyte as a model for the study of kidney podocyte biology and podocyte-associated diseases. This paper shows that insects possess a structure very similar, both anatomically and functionally, to the blood-filtering tissue of the vertebrate kidney, and raises the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors. It is also shown that fly orthologues of the major constituents of the slit diaphragm of the kidney form a complex of interacting proteins similar to the vertebrate slit diaphragm complex. The nephron is the basic structural and functional unit of the vertebrate kidney. It is composed of a glomerulus, the site of ultrafiltration, and a renal tubule, along which the filtrate is modified. Although widely regarded as a vertebrate adaptation1, ‘nephron-like’ features can be found in the excretory systems of many invertebrates, raising the possibility that components of the vertebrate excretory system were inherited from their invertebrate ancestors2. Here we show that the insect nephrocyte has remarkable anatomical, molecular and functional similarity to the glomerular podocyte, a cell in the vertebrate kidney that forms the main size-selective barrier as blood is ultrafiltered to make urine. In particular, both cell types possess a specialized filtration diaphragm, known as the slit diaphragm in podocytes or the nephrocyte diaphragm in nephrocytes. We find that fly (Drosophila melanogaster) orthologues of the major constituents of the slit diaphragm, including nephrin, NEPH1 (also known as KIRREL), CD2AP, ZO-1 (TJP1) and podocin, are expressed in the nephrocyte and form a complex of interacting proteins that closely mirrors the vertebrate slit diaphragm complex. Furthermore, we find that the nephrocyte diaphragm is completely lost in flies lacking the orthologues of nephrin or NEPH1—a phenotype resembling loss of the slit diaphragm in the absence of either nephrin (as in human congenital nephrotic syndrome of the Finnish type, NPHS1) or NEPH1. These changes markedly impair filtration function in the nephrocyte. The similarities we describe between invertebrate nephrocytes and vertebrate podocytes provide evidence suggesting that the two cell types are evolutionarily related, and establish the nephrocyte as a simple model in which to study podocyte biology and podocyte-associated diseases.