I am a clinician-scientist with the Division of Nephrology, McMaster University. My practice involves general nephrology and care of patients with chronic kidney disease and kidney failure receiving hemodialysis.

Research

My lab studies the molecular mechanisms involved in the development and progression of chronic kidney disease secondary to hypertension and diabetes, the most common causes of kidney failure in North America.  We primarily study kidney (mesangial) cell signaling to uncover pathways important in extracellular matrix production and hence kidney/glomerular scarring.  Results are tested in relevant animal models including the 5/6 nephrectomy model of hypertensive chronic kidney disease and type 1 diabetes models.

We currently have the following projects:

1. The role of Activins, members of the TGFβ superfamily, in diabetic and nondiabetic chronic kidney disease.  We have identified therapeutic efficacy of follistatin in protecting against the development of diabetic nephropathy and progression of chronic kidney disease in rodent models. Ongoing studies are assessing the regulation of follistatin, its potential therapeutic value in the metabolic syndrome and its potential as a novel antihypertensive. Studies are also elucidating the contribution of Activins to TGFβ1 profibrotic effects.
2. We have identified the metalloprotease ADAM17 as an important mediator of extracellular matrix production by mesangial cells in response to high glucose. Toxicity of ADAM17 inhibitors prevents their long-term use. We have identified the protein Lasp1 as a regulator of ADAM17 expression and activation in response to high glucose. Studies are now focused on understanding this regulation, and determining whether deletion of Lasp1 protects mice against diabetic kidney disease.
3. We have identified that the endoplasmic reticulum chaperone GRP78 is induced to translocate to the cell surface in diabetic kidneys and mesangial cells exposed to high glucose. In vitro, cell surface GRP78 regulates the profibrotic response to glucose. Current studies are investigating the mechanisms underyling this and whether blocking cell surface GRP78 is protective against diabetic kidney disease in vivo. Studies further include a focus on α2-macroglobulin as an activator of cell surface GRP78 in diabetes, for which targeting strategies are being developed.
4. In hypertensive rodents with chronic kidney disease, we showed that Pak1 is activated and upregulated in glomeruli. We also showed that Pak1 is important to matrix upregulation by mechanical stretch. Studies are now underway to determine whether mice with global Pak1 deletion are protected from kidney fibrosis in this model.

Funding

My lab is funded by the Heart and Stroke Foundation, Kidney Foundation of Canada and CIHR.

Publications

Via PubMed, http://www.ncbi.nlm.nih.gov/pubmed?term=Krepinsky%20JC