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Toronto-based research group uncovers mechanisms explaining sex-related differences in diabetic kidney disease

Researchers at University Health Network (UHN)’s Toronto General Hospital Research Institute (TGHRI) explored differences in male and female kidney cell metabolism, uncovering the mechanisms associated with sex-related outcomes in diabetic kidney disease.
Chronic kidney disease affects over 1 in 10 Canadians and is commonly caused by diabetes. Previous research has shown that males are at higher risk of diabetic kidney disease development and disease progression compared to females. Still, some females with diabetes also develop diabetic kidney disease. And the underlying reasons behind these sex-related differences are poorly understood and understudied.
 
Recent studies have emphasized the role of kidney tubular cells in the progression of diabetic kidney disease. Tubular cells are the primary cells responsible for producing energy in the kidney. They convert nutrients into energy through a process known as metabolism, producing essential molecules called metabolites. The metabolic activities of tubular cells are critical for kidney health and disease.
 
Dr. Ana Konvalinka, previous KRESCENT fellow, TGHRI Senior Scientist and senior author of the study, led an international team of researchers to explore metabolic differences in male and female tubular kidney cells.
 
Studying human tubular kidney cells, researchers found that male tubular cells had larger mitochondria—cell structures critical for generation of energy—and increased mitochondrial function. This heightened activity was due to more nutrients targeting a mitochondrial pathway known as the tricarboxylic acid (TCA) cycle. The TCA cycle is a fundamental pathway for generating energy for cells, but excessive activity can have detrimental effects. This was seen in the male cells, as they also showed increased rates of cell death, inflammation, and loss of mitochondria.
 
These distinct metabolic features were further enhanced in the presence of male sex hormones. Analyzing gene expression data sets of human kidneys, researchers discovered two transcription factors that interact with sex hormones or chromosomes to mediate metabolism in male kidney cells, particularly when exposed to high glucose to mimic diabetic conditions. These transcription factors present promising targets for developing therapeutic intervention.
 
Researchers also identified a potential protective factor in kidney cells—pyruvate. This metabolite is increased in female tubular cells and may act as an antioxidant to mitigate oxidative stress and subsequent cell damage in diabetic kidney disease.
 
“Sex-specific strategies that favour pyruvate accumulation while preventing excessive TCA cycle metabolism should be investigated as potential ways to prevent or improve the development of diabetic kidney disease,” says Dr. Sergi Clotet-Freixas, a previous KRESCENT fellow and previous postdoctoral researcher in the lab of Dr. Konvalinka and first author of the study.
 
Researchers further confirmed these results by analyzing over 5,800 blood samples from diverse groups of individuals with or without diabetes and kidney disease. In young males without diabetes, levels of TCA cycle metabolites were higher compared to females, suggesting increased mitochondrial activity. Elevated TCA metabolite levels were also found to be associated with the male sex, diabetes, and overall mortality in adults with chronic kidney disease. This suggests that these metabolites either have harmful effects on males with diabetes or are a result of harmful metabolic processes in their tissues.
 
In contrast, diabetic females without kidney disease had higher concentrations of pyruvate, better kidney function, and lower mortality.
 
Dr. Clotet-Freixas continues to investigate sex-specific therapeutic strategies to help patients with diabetes and diabetic kidney disease as a principal investigator at McMaster University – St. Joseph’s Healthcare and credits engagement in the KRESCENT program in his professional development.
 
‘I was awarded with the KRESCENT postdoctoral fellowship (2019-2022), which was a game changer for my training as basic scientist and kidney researcher. The KRESCENT program initiatives enabled me to interact regularly with clinicians and patient partners and taught me the importance of adding a translational component in my research studies. The team spirit and broad vision of KRESCENT inspired me to think out of the box and establish new collaborations, ultimately facilitating the clinical validation of our findings on sex and kidney metabolism in diabetic kidney disease’.
 
 “The power of teamwork is exemplified in this study, as we engaged collaborators from around the world who enthusiastically participated and shared samples and data from their research,” says Dr. Konvalinka. “What we have described is paradigm-shifting and suggests that mechanisms of kidney disease are distinct in males and females and require distinct solutions.”
 
This work was supported by the Canadian Institutes of Health Research, Canada Foundation for Innovation, The Kidney Foundation of Canada KRESCENT Program, UHN Foundation, University of Toronto CRAFT award, the Schroeder Arthritis Institute, the Natural Sciences Research Council, Ontario Research Fund, IBM and Ian Lawson van Toch Fund, the CIHR Strategy for Patient-Oriented Research (SPOR) Program, Can-SOLVE CKD, FONDO DE INVESTIGACIÓN SANITARIA-FEDER, National Institutes of Health, German Research Foundation, and Fonds de recherche du Québec (Santé). Dr. Ana Konvalinka is also an Associate Professor in the Department of Medicine and the Institute of Medical Science and Laboratory Medicine and Pathobiology, at the University of Toronto.