Investigations of Drosophila nephrocytes as central modulators of fly physiology in states of health and disease

• Applicant: Dr. Sybille Köhler
• Subject Area: Nephrology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 518261184

Drosophila nephrocytes belong to the fly kidney and filter the haemolymph. They share a high similarity with mammalian podocytes in their morphology and function, and are seen as podocyte homologues. In the fly, they are positioned around the oesophagus and along the heart tube. Due to this localisation and their constant exposure to changes in haemolymph composition and circulation, nephrocytes are in a unique position to sample and influence the haemolymph to help maintain a healthy physiology. This role of nephrocytes as ‘guardians of the haemolymph’ is likely to be essential for maintaining normal physiology, as all organs are bathed in the haemolymph and are dependent on its composition and physical properties such as circulation and pressure. This concept can easily be translated into the mammalian system as well, as all organs are supplied by blood and are dependent on its’ balanced and healthy state including composition and physical states. During chronic kidney disease, this balanced and healthy state is altered, as podocytes are injured and are finally lost into the primary urine, which leaves the capillaries in the glomeruli blank and results to changes in blood composition and circulation. Both, the loss of podocytes itself and the changes in blood composition and circulation, have a detrimental effect on other organs such as the heart. Interestingly, earlier studies in flies revealed an impact of nephrocytes on heart function and an involvement in the innate immune response. However, detailed mechanisms how nephrocytes and podocytes influence the function of other organs remains largely unknown until today. Within this proposal, we will utilize the model organism Drosophila melanogaster to unravel, whether nephrocytes act as central modulators of fly physiology. Diabetes and aging are well-known and major predisposing factors for chronic kidney disease. Hence, within this project, we will identify mechanisms how nephrocytes maintain haemolymph composition during these disease states and how they impact on other organs, including heart, gut and the immune system. By applying transcriptomic analysis, we intend to delineate the cell-cell-communication between nephrocytes and the other organs in greater detail. Using a translational approach, we will compare our proteomics fly data obtained within this project with available human data-sets of the Hamburg City Health Study and the European Renal cDNA Bank to identify novel risk factors, which are involved in regulating kidney, heart and immune system. This proposal will determine the central role of nephrocytes as modulators of physiology and help identify novel regulatory pathways in human health and disease.

• DFG Programme: Research Grants