The Kidney Foundation of Canada

Dr. Andras Kapus 

Dr. Andras Kapus 

St. Michael's Hospital, Ontario

Mechanotransduction pathways and fibrogenic reprogramming

2017-2019:  $100,000  |  Biomedical Research Grant  |  Category: Kidney Biology


Dr. Kapus obtained his MD (1986) and PhD (1990) in cell physiology at the Semmelweis University, Budapest Hungary. He was postdoctoral fellow at the Division of Cell Biology in the Hospital for Sick Children (1992-1995) in Toronto, and was then recruited as a basic scientist to the Toronto General Hospital Research Institute and Dept. Surgery in 1997. He was a Medical Research Council of Canada Scholar (1999-2004). Since 2005 he works at the St. Michael's Hospital/Keenan Research Centre (KRC) for Biomedical Research. He is a full professor (Dept. Surgery and Dept. Biochemistry) and the Associate Vice Chair of Research, Department of Surgery, at the University of Toronto, Head of Research Training Centre and Director of the Critical Care/Trauma/Inflammation Research Platform at KRC.

His research area is basic cell (patho)physiology and cell biology, specifically cellular stress signaling, volume and pH regulation, cytoskeleton remodeling and the role of the cytoskeleton in gene expression, epithelial-mesenchymal transition, and cell plasticity. He explores molecular mechanisms whereby the cytoskeleton regulates nuclear traffic of transcription factors and thereby cell fate and phenotype. This has strong relevance to his current major focus: the pathobiology organ (kidney) fibrosis.

He has published more than 145 peer-reviewed papers (H-index: 54), and has been continuously supported by the Canadian Institutes of Health Research (CIHR), The Kidney Foundation of Canada and the National Sciences and Engineering Research Council of Canada (NSERC). He has been involved in the graduate training of >50 students. He was the recipient of the Elsie Winifred Crann Memorial Trust Award for Medical Research, of a Medical Research Council of Canada scholarship, and also received the Premier’s Research Excellence Award, the Mel Silverman Mentorship Award and the James Waddell Mentorship Award.

Lay Summary

Chronic kidney disease (CKD) is a major health problem, which is often called an “epidemic” as it affects 12% of the population. In Canada 2.6 million people suffer from or are at risk for CKD, which most often develops as a consequence of common conditions such as diabetes and hypertension. In children the leading cause of CKD is the obstruction of the free flow of the urine due to various developmental defects. Unfortunately, we have no cure for CKD, which usually progresses toward chronic kidney scarring (called fibrosis). This process completely destroys the kidney architecture and function, necessitating dialysis or transplantation as the only means to prolong life. These “solutions” are associated with profound human suffering, are extremely expensive (e.g. dialysis costs more than $80,000/patient/year and there are over 23,000 dialyzed patients in Canada) and require lifelong medication, putting a huge burden on the patients and society alike.

Therefore, there is a dire need to understand the cellular and molecular basis of kidney fibrosis, since without this knowledge we cannot hope to reverse the disease process and restore function. Previous research from our lab and others has uncovered that in addition to certain chemical mediators, mechanical stress (such as increased fluid pressure, stretch or tissue stiffness) are critical triggers of the development of fibrosis. Such stress leads to transport of certain proteins (so called transcription factors) into the nucleus of kidney epithelial cells, and modifies the activity of genes. Ultimately this leads to the release of fibrosis-provoking compounds (cytokines), which induce scarring. Currently we do not understand how mechanical stress is sensed by kidney cells, and how this input leads to the reprogramming of genes. Here we propose to study the mechanisms that link the stress sensor molecules to the activation of mechanically regulated gene-modifying transcription factors in the nucleus. Specifically, we hypothesize that a certain ion channel, called TRPV4 regulates the activation of mechanically sensitive, recently discovered transcription factors (MRTF, TAZ, YAP). To test this hypothesis, we will employ a variety of cell and molecular biology techniques and animal models.

Identification of this mechanism has huge clinical relevance because TRPV4 can be inhibited by specific drugs, and such compounds (currently tested in humans for other conditions) might be efficient means to lessen or halt kidney fibrosis.