Program Directors
 

Award:  KRESCENT New Investigator Award
Institution: McMaster University
Year: 2024-2027

Study title: Can we protect the kidneys of people with diabetes or receiving a kidney transplant by modifying their metabolism?

Biography
Dr. Clotet-Freixas is an early career scientist with training in nephrology and diabetes research who is passionate about the study of cell metabolism and biological sex differences. His PhD work at University of Barcelona uncovered a novel link between androgens and the metabolism of human kidney cells. Following his PhD, Dr. Clotet-Freixas became a postdoctoral researcher at the University Health Network of Toronto, where he gained expertise in proteomics methods and in the metabolic profiling of animal and clinical specimens. Now as an independent researcher, Dr. Clotet-Freixas aims to deepen the understanding of biological differences between male and female kidney cells and tissue, thus guiding the development of more personalized therapies for kidney diseases. He has a special interest in the crosstalk between metabolism and epigenetics, and his research has two primary focus areas: (1) understanding the mechanisms mediating progression of diabetic kidney disease in males and females; and (2) understanding the mechanisms of acute kidney injury leading to allograft rejection in male and female kidney transplant recipients. Clotet-Freixas’ lab couples ‘omics’ methods with cell biology and biochemistry approaches to identify novel injury mechanisms and therapeutic targets. Dr. Clotet-Freixas is always open to new collaborative initiatives that enhance our ability to understand the impact of sex in a broader range of diseases.

Lay Summary
Our lab is trying to help patients with kidney disease in two different ways:
1) We are studying if we can protect the kidneys of people with diabetes by blocking a protein called KDM6A. People with diabetes often suffer from a complication called diabetic kidney disease (DKD). A very important cause of DKD is based on changes in the way kidney cells work and make energy. Unfortunately, we still don't know the reasons that make kidney cells work differently in people with diabetes. If we find the molecular reasons responsible for these changes, we will have a better knowledge of what causes injury to the kidneys of people with diabetes, and this knowledge will enable us to design better therapies to prevent DKD. In the lab, we study cells isolated from the kidneys of human donors. We found that when exposed to a diabetic challenge (which consists in high amounts of glucose) kidney cells have difficulties to use glucose and the amino acid glutamine to make energy properly. Moreover, we have found similar results in the kidneys of mice with diabetes. Glucose and glutamine are two of the favorite food options for cells, as they provide the energy for the kidneys to function. However, glucose and glutamine can also damage kidney cells, when present in abundance, as in diabetes. We are trying to explain why kidney cells consume glucose and glutamine differently in the setting of diabetes, and how this can be important in DKD. We have identified a protein (molecular actor) called KDM6A, that may control the use of glucose and glutamine by kidney cells, and their predisposition to injury in diabetes. In this project, we will study what happens when we remove KDM6A from kidney cells and from the kidneys of diabetic mice. This will help us determine whether KDM6A is important in controlling DKD. In the future, we may be able to manipulate KDM6A in patients, to maintain healthy kidney metabolism, and prevent DKD in people with diabetes.

2) We are also studying how kidneys of men and women respond differently to challenges that may occur to a kidney that is transplanted, such as low oxygen supply. We study how male and female kidneys change their metabolism differently under these circumstances, with the goal of finding what are the proteins that provoke lesions in male and female kidneys and that we could try to block to help the patients. Kidney transplantation is a vital treatment for end-stage kidney disease. Unfortunately, many transplanted kidneys fail due to a condition called ischemia reperfusion injury (IRI), that happens when they have not been receiving enough oxygen. One important aspect of IRI is that kidney cells are not capable of generating energy normally, and start relying more in a process that produces energy from glucose, known as glycolysis. In fact, in a human study we found that 4 proteins that facilitate glycolysis were increased in transplanted kidneys with signs of IRI. Importantly, males are more susceptible to IRI than females. We have also found that kidney cells obtained from men perform more glycolysis than cells from women, especially when we simulate IRI in these cells by exposing them to low oxygen levels or ‘hypoxia’. We think that the fact that male cells are more glycolytic may explain why males are more susceptible to IRI. Our research focuses on understanding how sex modulates the metabolism of kidney cells, and in particular glycolysis, during IRI. If we know how IRI affects kidney cells of each sex, we may be able to predict more accurately which transplanted kidneys are at higher risk of developing IRI. In this project, we will study male and female human kidney cells challenged with hypoxia, and male and female mice subjected to IRI. In these cells and mice, we will assess if the glycolytic proteins that were augmented in transplanted kidneys with signs of IRI are also affected by sex. We will also explore an avenue based on the use of drugs called SGLT2 inhibitors, which are used to treat diabetes and have shown promise in protecting kidneys from IRI. Our goal is to study if these drugs can prevent IRI in a sex-specific manner. In summary, we hope to identify the factors that contribute to IRI and determine the effectiveness of SGLT2 inhibitors in each sex. This knowledge may inspire new therapies to protect transplanted by preserving their metabolism.