Our group aims to characterise the pathophysiological mechanisms involved in the early stages of diabetic kidney disease and the development of albuminuria.

Specifically, we are interested in analysing the regulation of key glomerular epithelial cell (podocyte) proteins and their role in maintaining glomerular ultrafiltration. We address the regulation of insulin signalling and glucose transporter trafficking in podocytes and other insulin responsive cells, and study the mechanisms of podocyte loss in diabetic kidney disease.

Podocyte proteins and development of albuminuria

Podocytes together with the endothelial cells and the glomerular basement membrane maintain glomerular ultrafiltration. Adjacent podocytes are interconnected with a specific cell adhesion structure called the slit diaphragm. The slit diaphragm consists of transmembrane proteins belonging to the cadherin and immunoglobulin superfamilies and intracellular adaptor proteins that link the membrane proteins to the underlying actin cytoskeleton and signalling cascades.

Nephrin, a member of the immunonoglobulin superfamily, is a key structural component of the slit diaphragm. It has been shown to be downregulated or mislocalized in various albuminuric diseases, including diabetic kidney disease. Nephrin associates with the intracellular adaptor proteins CD2AP and PACSIN2 and the small GTPase septin 7. We address the mechanisms by which nephrin is downregulated or mislocalized in proteinuric diseases and study the mechanisms by which podocyte proteins regulate glomerular ultrafiltration.

Insulin signalling

Insulin resistance is associated with increased risk for the development of diabetic kidney disease. The binding of insulin to its receptor on the cell surface initiates a complex intracellular signalling system, activating, for example, phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways, which are differentially regulated. The effect of insulin on glucose uptake is mediated mainly through the PI3K pathway.

Our aim is to study the regulation of insulin signalling in insulin-responsive tissues in normal conditions and in diabetes. We address the role of lipid phosphatase SHIP2 in podocytes and other insulin responsive cells. Furthermore, we aim to characterize novel molecules that associate with the development of insulin resistance and to identify small molecules that affect their function. These small molecules can be used to develop new treatments for insulin resistance, type 2 diabetes and its complications.

Glucose transporter trafficking

Elevated levels of glucose can cause cellular damage through different mechanisms such as the production of reactive oxygen species (ROS) and the formation of advanced glycation end products (AGEs). On the other hand, insulin signaling is essential for normal kidney function and several studies show that many, although not all, insulin sensitizers reduce albuminuria.

Podocytes, muscle cells and adipose cells are able to take up glucose in response to insulin. Insulin stimulation activates the translocation of glucose transporter 4 to the plasma membrane and glucose uptake into cells. The final phase of the pathway consists of several distinct steps involving targeting, docking and fusion of glucose transporter 4 -containing vesicles to the plasma membrane. We characterize the regulation of glucose transporter trafficking in insulin-responsive cells and study how the various steps of glucose transporter targeting, docking and fusion are regulated.

Metabolic disorders and kidney dysfunction

Overweight and obesity are serious health problems worldwide and their prevalence is increasing. Obesity is associated with an increased risk of developing insulin resistance and type 2 diabetes. Furthermore, obesity causes cellular stress that predisposes to chronic kidney disease. Therefore, there is a high demand to better understand the biochemical basis of obesity and its associated metabolic disorders, and to come up with novel treatments.

We are interested in identifying molecules that regulate energy homeostasis and characterizing the pathways that these molecules regulate. Specifically, we are interested in tankyrases, members of the poly-ADP-ribose polymerase family. We investigate the molecular mechanisms, which underlie the regulation of metabolic homeostasis by tankyrases. We also aim to identify small drug-like molecules that target the metabolic pathways and thereby improve energy metabolism and insulin sensitivity and, consequently, prevent or slow down the development of obesity, diabetes and its complications.


Metabolism and kidney function - studies in zebrafish

Zebrafish has emerged as a new model to study obesity, diabetes and its complications, and to perform pharmaceutical screenings. Importantly, the zebrafish pronephros is composed of a full range of cell types typical for higher vertebrate kidney, and many of the pathways and cellular processes involved in kidney development are highly conserved. Conservation of the drug-binding regions between human and zebrafish proteins makes zebrafish an excellent in vivo model to discover small molecules with potential effects on human diseases.

We utilize the zebrafish model to address the role of the proteins involved in the regulation of metabolic processes and kidney function. We overexpress or knock down these proteins and analyse the effect on the metabolism and kidney ultrafiltration. We also use the developed zebrafish models for small molecule screenings to identify compounds that specifically affect the disease processes.