Understanding mechanisms of acute kidney injury (AKI) and its impact on distant organ function

Ischemia-reperfusion injury is a common cause of tissue damage such as acute kidney injury (AKI), myocardial infarction and stroke. Distant organ dysfunction often coexists with AKI, which potentiates the already high risk of AKI-associated morbidity and mortality.  Cardiovascular complication still represents a main cause of death in AKI patients. However, therapeutic options for AKI and its complications are limited. Dr. O’s laboratory has identified that ischemia-reperfusion leads to oxidative stress and inflammatory response not only in the kidney but also in other organs such as the liver and in the circulation. The focus of their current research is on understanding the cellular and molecular mechanisms involved in kidney and distant organ injury, the impact of AKI on cardiovascular function and sexual difference in organ function. Understanding the mechanisms of AKI-induced distant organ injury is important in identifying new therapeutic targets and ultimately improving clinical outcomes.

Understanding mechanisms of metabolic disease – Non-alcoholic fatty liver disease (NAFLD) and the effects of natural products

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease that is strongly associated with obesity and type 2 diabetes mellitus. The prevalence of NAFLD is 15-30% in general population and 70-90% in patients with type 2 diabetes and obesity. If untreated, NAFLD may further progress to liver failure and cancer. Aside from lifestyle modification (weight loss), other therapeutic options are limited. NAFLD is a complex and progressive liver disorder. The mechanisms mediating NAFLD pathogenesis are not well understood. Recent studies from Dr. O’s laboratory has identified that altered homocysteine, hydrogen sulfide and glutathione metabolism, increased hepatic lipid biosynthesis can contribute to fatty liver development, systemic oxidative stress and chronic inflammation.  Currently, Dr. O’s laboratory conducts studies to identify compounds (i.e. berberine, tyrosol, polyphenols) and extracts prepared from agricultural products that affect cellular and molecular targets in nutrient absorption and metabolism in the intestine and liver, regulation of sulfur-containing amino acid metabolism and oxidative stress.

Understanding the impacts of dietary components on nutrient absorption and metabolism

Vitamins are essential micronutrients for humans and animals. Folic acid is a synthetic form of folate (vitamin B9) that is used in fortified foods, supplements and animal feeds. Folate/folic acid is a key nutrient essential for the normal growth and development of humans and animals. Folate deficiency can occur when dietary intake is inadequate, intestinal absorption is decreased, liver function is impaired or when body need is increased. Although Western foods and animal feeds are fortified with folic acid, some components in energy-dense diets or endotoxin and mycotoxin-contaminated staple foods or feeds may interfere with folate homeostasis and compromise its cellular function. Dr. O’s laboratory has observed that chronic consumption of a high fat diet causes folate deficiency, obesity and fatty liver in mice while folic acid supplementation can restore the folate level and improve liver function. Although folic acid supplied by Western diet is sufficient to meet the requirement of generally healthy people, its levels may not be adequate for individuals with fatty liver disease. Funded by NSERC, Dr. O’s laboratory investigates (1) how dietary-derived factors influence folic acid absorption in the intestine and its metabolism in the liver; (2) how oxidative stress and cellular signaling pathways are involved in nutrient balance. Their long-term goal is to develop a research platform to identify how dietary components (ranging from nutrients to contaminants and additives) affect nutrient bioavailability and to investigate whether mitigating negative influences of dietary factors on folate and other nutrient absorption and metabolism can optimize their biological functions in humans and animals. Better understanding of these effects will equip the government and industry with new strategies to optimize the intake of dietary nutrients.

Connie WH Woo (PhD student), Sun-Young Hwang (PhD student), Nan Wu (PhD student), Jennifer E Enns (MSc student) and Lindsei K Sarna (PhD student) received

• Research Manitoba (formerly Manitoba Health Research Council) Studentship

Nan Wu (PhD student) and Victoria Sid (PhD student) received

• Canadian Society of Atherosclerosis, Thrombosis and Vascular Biology Young Investigator Award at the Canadian Cardiovascular Conference

Victoria Sid (PhD student) received

• Mark and Pat Smerchanski Studentship

Peggy Wang (PhD student) received

• BMO Student Endowment Fund Scholarship

Connie WH Woo (PhD student) and Nan Wu (PhD student) received

• Major Research Award (Manitoba) in Cellular Physiology, Canadian Student Health Research Forum

Dr. O’s laboratory would like to gratefully acknowledge the following funding agencies and foundations:

• BMO (Studentships)
• Canadian Institutes of Health Research (CIHR)
• GETS (Studentships)
• Heart and Stroke Foundation
• Research Manitoba (formerly Manitoba Health Research Council)
• Manitoba Medical Services Foundation
• Manitoba Pork Council
• Natural Sciences and Engineering Research Council of Canada (NSERC)
• Mark and Pat Smerchanski Studentship Grant (PhD studentship)
• St. Boniface Hospital Foundation (Molson’s Women’s Heart Health Initiative)
• University of Manitoba (Studentships)