Research in nephrology has long been limited to the extreme situations of kidney failure or kidney transplantation. Until recently, the damaging effect of inflammation on kidney function had been little studied. With his team, Pierre-Louis Tharaux has transformed the state of knowledge in this area: his work has revealed that certain cells called podocytes play a key role in the tolerance of the kidneys to inflammation.
How did you discover the role of podocytes as key cells in the mediation of inflammation and the development of kidney injury?
Almost by accident! During my post-doctorate work in the United States, then as a young recruit to Inserm on my return to Paris, I studied various inflammatory molecules. I had observed that animals without certain inflammatory growth factors did not present with kidney injury. By studying this mechanism, I showed that these inflammatory molecules were not directly involved in causing the kidney injury: in actual fact, they activate an inappropriate response in the podocytes, which begin to produce other mediators and sustain the destructive inflammation. Podocytes normally control the glomerulus, i.e. the part of the kidney that filters blood and produces urine. They are usually latent, but inflammation causes them to proliferate uncontrollably. This inappropriate response is responsible for causing the injuries that prevent the kidney from continuing to function normally. Podocytes therefore play a key role in the tolerance of the kidneys to inflammatory and metabolic stress. They constitute a prime target for improving the prognosis of many kidney diseases.
What are the main diseases involved in your work?
Primarily extracapillary glomerulonephritis, which is a rare but serious disease caused by various diseases with an autoimmune inflammatory component. Then focal segmental glomerulosclerosis, which affects more people. But the research continues! With our growing understanding of the role of kidney cells and podocytes, we are seeing a renaissance in glomerular disease research. Our work has contributed to this.
In other glomerular diseases, the data show that podocytes do not proliferate but actually die. We must therefore continue to research why these diseases are different, and try to find out how we can improve the functional survival of these glomerular cells.
In what ways has funding from the European Research Council (ERC) helped your work?
The €1.5 million that we were granted in 2012 have allowed us to use innovative genomic and proteomic methods to which we would not otherwise have had access. These have enabled us to study the cellular pathways that determine podocyte behavior. This is how we also identified the fundamental mechanism, called autophagy, that protects certain kidney cells (podocytes and vascular cells) in some common diseases such as diabetes and hypertension.
We have also discovered that PPAR-g is a key transcription factor in podocyte protection. If you suppress the gene that codes for PPAR-g in mice, the podocytes die and the injuries pile up. From a therapeutic perspective, we have also been able to show that an agent that stimulates PPAR- activity, such as pioglitazone, makes podocytes tolerant to inflammation and thus prevents kidney failure. This therapeutic avenue requires further exploration.
ERC support has greatly sped up the progress of our discoveries. It has enabled us to take risks and to test more hypotheses in an area where data are still inadequate. Not to mention the synergies provided by communication with other ERC grant holders. This funding represents recognition for work in a promising area and for taking risks, but it is also a label of quality and increased visibility that has made it easier for us to develop international collaborations.
Find out more about Pierre-Louis Tharaux and his work
Pierre-Louis Tharaux co-directs the GPCRs and Tyrosine Kinase Receptors: Roles and Interactions in Development and Disease group within Inserm Unit 970/Université Paris Descartes, Paris Cardiovascular Research Center (PARCC).