The kidney is one of the main sites of blood volume regulation,osmoregulation and excretion in vertebrates. Its functional unit is the nephron, which can be found in countless copies in the kidney. Nephrons consist of a filtering element that is partially formed by podocyte cells, and a tubule, which reabsorbs everything that is needed by the body and secretes the remaining fluid as urine. Insect excretory systems serve similar functions but lack a nephron-like unit. Instead, insects are equipped with more independently functioning organs: Malpighian tubules for secretion and reabsorption and nephrocyte cells for filtering and disposing of substances that Malpighian tubules have difficulty dealing with. In a recent paper published in Nature, a team working with Helen Skaer at the University of Cambridge reports intriguing similarities between vertebrate podocytes and insect nephrocytes.
Knowing that both cell types are involved in filtration processes, Skaer and her multinational team addressed the question of whether the filtration units of podocytes and nephrocytes exhibit anatomical similarities. Undertaking a comprehensive ultra-structural study on Drosophilanephrocytes, the team found structures in the insect nephrocyte that are very similar to the vertebrate podocyte's `slit-diaphragm' structure, which is part of the kidney's filtration mechanism. In the vertebrate kidney adjacent podocytes form delicate finger-like projections that interdigitate and enclose a tiny ball of blood vessels called the glomerulus. The fingers do not surround the glomerulus entirely but leave open narrow gaps (called filtration slits) that are bridged by the `slit diaphragm', a structure composed of cell surface proteins. Looking at insect nephrocytes, which absorb potentially harmful substances, Skaer's team found infoldings in the plasma membranes forming small cavities. Similar to the situation in podocytes, the cavities'entrances are narrow gaps that are bridged by cell surface proteins forming the nephrocyte diaphragm.
Working with Drosophila also allowed the scientists to look for molecular similarities between the vertebrate and insect diaphragm structures. As the genes encoding the major constituents of the vertebrate slit diaphragm were known, Skaer and her colleagues were able to examine the expression of corresponding genes in Drosophila. They found several of these`orthologous' genes expressed in the insect's nephrocytes. In vertebrates two of the major components of the slit diaphragm are nephrin and NEPH1, which interact across the filtration slit to bridge the gap. When the team took a closer look at these structures by immunoelectron microscopy, they found the Drosophila nephrin and NEPH1 orthologues in close proximity at the nephrocyte diaphragm. Using yeast two hybrid analysis and co-immunoprecipitation they finally showed that the Drosophilaorthologues of five known diaphragm components, including nephrin and NEPH1,form a complex that closely resembles that of the vertebrate diaphragm. One of the major advantages of using Drosophila for this study is that it is possible to knock-out the expression of specific genes, offering Skear and her colleagues the opportunity to knock-out expression of some of the diaphragm genes. Accordingly, when they generated flies lacking either the nephrin or the NEPH1 orthologues, the nephrocyte's diaphragm was lost and its filtration function was significantly impaired, similar to what is observed when these proteins do not function properly in the vertebrate kidney.
In view of the striking functional, anatomical and molecular similarities between the slit-diaphragms of vertebrate podocytes and insect nephrocytes, it is tempting to speculate whether these cells derive from a common progenitor,although the answer to this is still pending. In any case, Skaer and her team have established a potent genetic model for investigating podocyte-related diseases.
