What The human kidneys generate 180L of human primary urine every day. This is achieved by continuous ultrafiltration of the blood. Podocytes are specialized cells at the kidney filtration barrier that are constantly subjected to changing filtration and shear stress. Failure to withstand this pressure leads to disease. Our previous data has shown that metabolic alterations proceed the development of disease of the filtration barrier, but its relevance is unclear. The overall aim of this project is to metabolically enforce podocytes to withstand the increased mechanical forces in glomerular filtration in disease. Why We do not know if podocytes can be regenerated or how they can be protected in disease. In addition, podocyte metabolism is poorly understood. By charting the interconversion of molecules in podocytes, we will obtain uptake and kinetic data that are altered in disease. Our project will provide not only new insights into the origins of kidney disease and proteinuria, but also set the precedent for active metabolic modulation of podocyte function. How We will use mass spectrometry coupled to functional assays to analyze the physiology of the data. We will develop novel methods to isotope-trace bioactive metabolites in vivo and in vitro and analyze altered podocyte metabolism in response to flow and shear stress. SSR Because of the extremely high prevalence of kidney disease, even minor changes in management will have a large societal impact. The obtained molecular signatures can drive innovation and be exploited in both public and private space.