Research Award Recipients

Delineating the Role of the Mitochondrial Protein Prohibitin-1 in the Kidney’s Biology and its Dysregulation in New-Onset and Progressive Diabetic Kidney Disease – A Novel Approach

Co-applicant(s): Yeshika Bhatia

Lay Abstract

Background: Diabetic kidney disease is a major chronic kidney disease and a growing health problem worldwide. Currently, there is no cure for this disease and the treatment primarily focuses on disease management. Over a period of time, patients with diabetic kidney disease starts to lose their kidney function and may progress to end-stage kidney disease when the kidneys are no longer able to work at a level needed for day-to-day life. The economic cost of chronic kidney disease on the national health care system is staggering, which is over Amount: $40 billion per year in Canada. Together, this highlights the need to advance our knowledge of new-onset and progressive diabetic kidney disease to develop a multipronged strategy to prevent or delay these processes while developing curative therapeutics. The kidneys are the most energy-demanding organs in the human body under resting conditions, a demand which is met by their enriched mitochondrial contents – the powerhouse of the cell. Therefore, it is not surprising that mitochondrial abnormalities in the kidneys are the main driver in the development and progression of acute & chronic kidney disease and therefore a potential therapeutic target for kidney diseases. However, there are knowledge gaps in our understanding of the identity of key mitochondrial proteins that are dysregulated and the precise role of dysregulated mitochondria in the disease process.

Purpose: A discovery in my laboratory have revealed the identity of a mitochondrial protein called prohibitin-1 in these processes. Novel genetically engineered mouse models expressing prohibitin-1 mutants that we have developed in-house display compromised mitochondrial structure and function, and are susceptible to develop diabetic kidney disease, which mimics the features of this disease in humans, including biological sex-related differences. Impaired prohibitin-1 levels in the kidneys was also found in other established preclinical models this disease. While these findings are new and exciting, they raise important questions. What are the molecular mechanisms by which prohibitn-1-linked functions regulate kidney cell biology, and why does their loss result in increased risk for diabetic kidney disease onset and progression? My team will utilize this unique opportunity and define why dysregulation of prohibitin-1 cause mitochondrial abnormalities and increased susceptibility to diabetic kidney disease. Our goal is to answer these questions and explore whether restoring prohibitn-1 status in the kidneys would restore mitochondrial status and prevent or delay diabetic kidney disease onset and progression.

Method: To accomplish the goals of this proposed research would require a systematic and comprehensive analysis of the cellular and molecular changes in main cell types in the kidneys from our novel prohibitin-1 mutant mouse models that are affected in health and disease processes. In addition, we will explore whether restoring prohibitin-1level and function in renal cells & tissues in these preclinical models would repair mitochondrial damages and reverse susceptibility to diabetic kidney disease, including new-onset and progressive diabetic kidney disease.

Anticipated Outcomes: Research findings are expected to provide new insights into the role of prohibitin-1 in renal mitochondria and its dysregulation in diabetic kidney disease. The new knowledge gained here could offer new opportunities for disease modification and the improved management of diabetic kidney disease, and expected to open new research directions in this field. As a corollary, we will establish new preclinical research tools in this field.

Patient Engagement: This research proposal is based on a new discovery made in my research program. Particularly, an important but unexplored property of prohibitin-1, which is virtually unknown in current literature. We are at early stage in this fundamental research, therefore, the patient engagement component is not applicable at this time.

Relevance to Patients/Community: If we find a way to repair and restore the function of the main kidney cells types (which are impaired in diabetic kidney disease) that is expected to have substantial impact in improved management of diabetic kidney disease and better treatment outcomes.

Conclusion: This is a new project based on promising discovery in my lab about a key mitochondrial protein as a potential therapeutic target for DKD.