Our research goal is to understand the fundamental mechanisms of kidney disease in order to develop novel therapies for renal failure. To this end, we use integration of mass-spectrometry based proteome and metabolome analyses in order to pinpoint the precise mechanisms determining glomerular fate and kidney tissue heterogeneity, and to investigate their impact in a hypothesis-driven manner from mouse to man.

Here, I will present a global view on mechanistic actions of SGLT2 (Slc5a2) inhibitors by multi-layered omic integration. SGLT2 inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood. Previous studies have only analyzed individual organs, and the late-stage pathology potentially reflected tissue remodeling secondary to metabolic benefits. Here, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis after one week of SGLT2i treatment of non-diabetic as well as early diabetic mice, by integrating signatures from multiple metabolic organs and body fluids. The results revealed that metabolic communication by the SGLT2i reduced circulating waste products like p-cresol sulfate and thereby the need for renal detoxification, which combined with less proximal tubule glucotoxicity and a broad downregulation of apical transport activity provides a metabolic explanation for kidney and cardiovascular protection.