The role of podocytes in the regulation of the single nephron glomerular filtration rate

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The human kidney consists of 1 million small filtering units, the nephrons. Each nephron contains a glomerulus with a capillary tuft in which blood components are filtered. The kidney filter consists of three layers, the endothelium, the basement membrane and the slit diaphragm, which spans the distance between the podocyte foot processes. The filtration in each single nephron is regulated by alteration of the resistance of afferent and efferent vessels. The role of podocytes in regulation of the single nephron glomerular filtration rate hasn¿t been studied in detail so far. Oscillating calcium levels have been demonstrated in podocytes and they contain contractile element. This suggests, that podocytes contract on a regular basis. In my experiments I will study intact kidneys ofliving mice by multiphoton microscopy, this approach will allow to study morphology and function at the same time. I will visualize the fluctuations in intracellular calcium levels in podocytes by calcium-sensitive dyes. The podocytes will be loaded by an innovative technique of injecting the dyes selectively into the renal artery. To examine the influence of podocytes on glomerular filtration without confounding effects, I will use a genetically modified mouse with an artificial receptor (RASSL), whose expression is restricted to podocytes. Its activation rises intracellular calcium levels. To study podocyte morphology and calcium levels during disease states I will utilize two mouse models of focal segmental glomerulosclerosis (FSGS). The first model is the pharmaceutical induction of FSGS by injection of Adriamycin, the second one the genetic knockout of myosin 1E in a mouse. Both models lead to podocyte damage and loss. Using these mouse models I will look into reactions of neighboring podocytes to these insults.