Understanding the metabolic landscape in the human kidney in diabetes

The Department of Diabetes at the School of Translational Medicine (STM) is a part of Monash University’s Faculty of Medicine, Nursing and Health Sciences (FMNHS). The STM is part of the Alfred Research Alliance in Prahran, co-located with the Alfred Hospital and the Baker and Burnet Institutes. STM is a core hub for translational research and medicine. STM's research is highly collaborative, both within the Alfred Research Alliance precinct, nationally and internationally with world leaders in biomedical and clinical research. With such close links to health care providers we are able to rapidly move towards health outcomes in improved patient care. Diabetes is the most common cause of end stage renal disease (ESRD) worldwide. Almost 40% of people requiring renal replacement therapy (dialysis/kidney transplantation) in Australia are people living with diabetes. Individuals with diabetic kidney disease (DKD) carry a higher risk of developing comorbidities such as cardiovascular disease and indeed, renal dysfunction is the major predictor of all-cause mortality in the diabetic population. Current therapies, including renin-angiotensin system (RAS) inhibitors and Sglt2 inhibitors, do not fully prevent, but rather postpone progression to ESRD. Thus, it is critical to find new biomarkers or therapeutic targets to address these unmet clinical needs. The kidneys are a fuel-hungry organ and as a result the mitochondria play a key role in the maintenance of kidney function. Previous studies have shown features of metabolic programming in the kidney in animal models of diabetes, including a decline in mitochondrial function (1-5) and lipid accumulation, which promotes susceptibility to DKD. However, this field has suffered from a lack of clinical translation due to the absence of studies exploiting living donor human kidney biospecimens from individuals with diabetes with which to define the metabolic landscape. We have now established a program of translational research involving the collection of fresh kidney biospecimens from subjects with and without diabetes in which to map the disease phenotype at the molecular level. The proposed research will address the absence of knowledge of the mitochondrial phenotype in human DKD by studying kidney tissue obtained from healthy individuals and subjects with diabetes who do not progress to DKD versus those with various stages of DKD. The overall aim of this proposal is to define the metabolic landscape in the human kidney, by studying kidney tissue from non-diabetic individuals, subjects with diabetes who do not progress to DKD versus those who progress to DKD in order to understand the basis of the progression of the disease process. This knowledge will identify novel targets of therapy and will lead to the development of new drugs better designed to prevent the progression to end stage kidney disease, ultimately leading to improved patient care. Techniques: Human kidney biospecimen collection and processing, isolation of glomeruli/tubules, cell culture, mitochondrial isolation, biochemical assays, high resolution respirometry, metabolic tracing studies, western blotting, qPCR, ELISA, imaging, proteomics, bioinformatics. References 1. Coughlan MT, et al.: Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis. Diabetes 2016;65:1085-1098 2. Coughlan MT, et al.: Mapping time-course mitochondrial adaptations in the kidney in experimental diabetes. Clinical science 2016;130:711-720 3. Coughlan MT, et al.: Combination therapy with the advanced glycation end product cross-link breaker, alagebrium, and angiotensin converting enzyme inhibitors in diabetes: synergy or redundancy? Endocrinology 2007;148:886-895 4. Coughlan MT, et al.: RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. Journal of the American Society of Nephrology : JASN 2009;20:742-752 5. Tan SM, et al.: Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility. Diabetes 2020;69:83-98