The Kidney Foundation of Canada

Professor Keir Joe Menzies 

Professor Keir Joe Menzies

University of Ottawa, ON

Removal of mitochondrial health to improve the outcome of acute kidney injury

2017-2019:  $99,990  |  Biomedical Research Grants  |  Category: Renal Failure


Keir Menzies is an assistant professor at the Interdisciplinary School of Health Sciences, Faculty of Health Sciences, and is cross-appointed to the department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa. His research examines metabolism in various organs with a special interest in energy-signalling pathways that support kidney function and health. By understanding these signalling pathways he hopes to create new treatment options for metabolic dysfunction in kidneys during disease or injury. Previously, he has helped define various metabolic pathways that are controlled by the energy-sensing group of NAD+-dependent enzymes named sirtuins. Using nutraceutical or pharmaceutical strategies that boost tissue NAD+ levels, followed by the activation sirtuin enzymatic activity, his research has led to new treatments for metabolic dysfunction in muscular dystrophy, non-alcoholic fatty liver disease and stem cells during aging in mice. Optimization of these treatment strategies will eventually include mapping whole body NAD+ homeostasis as a predictive biomarker of metabolic dysfunction during injury, disease and aging.

Lay Summary

Acute kidney injury is the most common renal disease with no effective treatment. Acute kidney injury affects 3-7% of hospitalized patients with a patient mortality rate that exceeds that of breast and prostate cancers, heart failure and diabetes combined. After adverse kidney events or toxic cancer treatments in humans, there is a pronounced loss and dysfunction of various cells within the kidney that results in the evolution of acute kidney injury.

Importantly, certain kidney cells are extremely rich in mitochondria, the organelle of a cell that provides energy, and are therefore sensitive to the decline in mitochondrial health that occurs during acute kidney injury. Mitochodnrial health relies greatly on a family of proteins named sirtuins, which may therefore be an ideal target for treating injured kidney cells. Interestingly, the activity of sirtuins relies on a cellularly-limited metabolite called NAD+, thus we hypothesize that treatments that boost NAD+ levels will possess clinical potential in acute kidney injury. These NAD+ treatments can include diet supplements of nicotinamide riboside (NR), which is a known component of certain foods such as milk, and is a precursor for NAD+ production. NR has proven to be a very effective at rasing NAD+ levels and sirtuin activity in cells to enhance metabolism. In fact, over the last year our research alone has shown that NAD+ boosters can treat metabolic diseases, improve stem cell health during aging and even extend the lifespan of mice. Beyond NR there are other NAD+ boosters that include inhibitors for a family of proteins called PARPs, which consume NAD+, and a novel inhibitor for an enzyme that diverts precursors away from NAD+ production, called ACMSD.

Thus, we propose to explore and compare the ability of these NAD+ boosters to improve mitochondrial health in two mouse models of kidney injury. We plan to treat rodents with NAD+ boosters following kidney injury in a therapeutic approach, mimicking a real-life treatment for a sudden acute kidney injury event. We expect that NAD+ boosters will help recover mitochondrial health in kidneys and improve the outcome of this type of injury. We will examine the signaling events that occur with this treatment strategy using a primary cell culture model of kidney cell injury. As each of the NAD+ boosters we propose to use can be administered in food, this approach could have immediate translational potential to the clinic. In addition, NR is already sold as a food supplement and PARP inhibitors, such as Olaparib (used in this study), are currently being used in combinatorial cancer therapies.