We specifically focus on central proteins in podocytes (glomerular epithelial cells) and kidney tubule epithelial cells and their roles in maintaining kidney function. We address the regulation of glucose uptake in insulin-responsive cells, including myocytes and podocytes, aiming to understand the mechanisms leading to the development of insulin resistance and its role in the development of kidney dysfunction. We also search for new drug targets and drug leads for type 2 diabetes and its complications.
We study the role of proteins expressed in podocytes as regulators of glomerular ultrafiltration using transgenic and knockout mouse models. We challenge the mice by inducing, for example, obesity and diabetes to define the significance of these proteins in the development of kidney dysfunction under metabolic stress. Using cultured podocytes, we study the molecular mechanisms whereby the proteins regulate podocyte function.
We are also interested in identifying proteins that regulate energy homeostasis in proximal tubule epithelial cells and characterizing the pathways that these proteins regulate. We aim to identify small drug-like molecules that target these pathways and thereby improve the energy metabolism. Ultimately, our goal is to prevent or slow down the development of kidney injury using mouse models of obesity and diabetes.
We investigate novel small molecule compounds as drug lead candidates for the treatment of type 2 diabetes and prevention of diabetic kidney disease. We investigate whether the compounds enhance glucose uptake into muscle cells and study their metabolic effects. We also study the ability of the compounds to prevent injury of podocytes and kidney tubular cells.
Using animal models of obesity and diabetes we analyze the ability of the compounds to improve insulin sensitivity and prevent the development or progression of diabetic kidney disease. We are also interested in demonstrating the exact molecular mechanisms via which the compounds act. This may unravel new molecules or mechanisms involved in the regulation of insulin signaling and glucose transporter trafficking, and pathological changes leading to the development of diabetic kidney disease.
We use immortalized cell lines (podocytes, proximal tubule epithelial cells, myocytes), transgenic, knockout, and diabetic animal models, and ex vivo human kidney tissues as research models. We carry out expression and localization analyses, lentiviral overexpression and knockdown studies, protein-protein interaction and protein trafficking studies, and glucose uptake assays. In the projects with drug leads, we carry out viability and cytotoxicity assays, flow cytometry-based assays (e.g., apoptosis), and ligand-target interaction assays, such as CETSA (Cellular Thermal Shift Assay). We also carry out experiments with podocytes under experimental fluid flow shear stress. In animal studies, we utilize kidney challenge models and define general metabolic parameters and kidney function of the mice.