Chris Kennedy

ckennedy@uottawa.ca

Senior Scientist, Chronic Disease, Ottawa Hospital Research Institute

Associate Professor, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa

B.Sc. Biochemistry (University of Ottawa, 1992)

Ph.D. (University of Ottawa, 1996)

Biographical Sketch

Dr. Kennedy's research has focused on the function and regulation of prostaglandin receptors in the regulation of blood pressure and progression of renal disease. He received his Ph.D. from the University of Ottawa in 1996 under the supervision of Drs. Pierre Proulx and Richard Hébert. He carried out his postdoctoral training in the Division of Nephrology at Vanderbilt University, under the supervision of Dr. Richard Breyer, from 1996 to June 2000. Dr. Kennedy is currently a Research Scientist within the Kidney Research Centre at the Ottawa Hospital Research Institute.

Raison D'être Why study the kidney??

Kidney dialysis strategies have improved dramatically over the years, yet our ability to effectively prevent kidney disease has not progressed as far. Our capacity to attack this problem in the coming years will undoubtedly depend upon a greater understanding of the complex molecular mechanisms underlying kidney disease.

In the mammalian kidney, urine formation begins with filtration of large amounts of fluid from the blood through the glomerulus. Because of its unique architecture and role, the glomerulus is the target of many renal nephropathies, including focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, hypertension, minimal change nephropathy, etc. Podocytes are specialized epithelial cells that stabilize the glomerular membrane and contribute to specific characteristics of the glomerular filtration barrier. Under certain pathological conditions, the glomerular podocytes can become damaged allowing passage of large proteins into the urinary space (proteinuria).

Non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit the production of prostaglandins (PGs) have been shown to effectively reduce proteinuria in both experimental animals and humans. However, the molecular mechanism is unknown. PGE2 is a particularly important metabolite in the kidney where it modulates vascular tone and fluid/electrolyte balance via interactions with at least four distinct E-Prostanoid receptor (EP) subtypes (EP1-4). Recently mRNA expression of both the EP4 and EP1 receptors has been demonstrated in the kidney, with localization in the glomerular podocytes. However, the lack of suitable agonists and antagonists has restricted the evaluation of the physiological role of these EP receptors in vivo.

Research Themes:

1. To uncover the roles of prostaglandin receptors under normal and pathophysiological states in the kidney (references 1,4-7).

2. To establish and evaluate mouse models of human kidney disease (reference 3).

Modus Operendi

My lab employs both transgenic and gene targeting approaches in concert with animal physiology studies to address the research themes listed above.

Theme 1. We are using the Cre/loxP system to specifically delete the prostaglandin EP4 receptor from podocyte cells within the kidney glomerulus. To achieve this goal, we are currently generating transgenic mice expressing Cre-recombinase in a podocyte-specific manner under the control of the nephrin promoter. Nephrin expression is restricted to podocytes thereby making its promoter an attractive candidate to drive Cre expression. We have obtained mice with a floxed EP4 gene from Drs. Matthew Breyer and André Schneider at Vanderbilt University. The nephrin-Cre mice will be bred with the loxed EP4 mice in order to disrupt the PG EP4 receptor exclusively in the podocytes. These mice will be examined for their susceptibility to various challenges in order to test the hypothesis that the PG EP4 receptor subtype mediates the physiological actions of PGE2 in the glomerular podocyte under basal and pathophysiological states. Demonstration of a critical role for the EP4 receptor subtype in the proper development and function of podocytes within the context of various renal disease states, such as those in which proteinuria is exhibited, may identify a novel therapeutic target.

Theme 2. Additionally, the nephrin promoter will allow for the development of transgenic mouse lines in which various genes of interest are either overexpressed or mutated (a dominant negative or gain of function effect) in order to recapitulate human disease states in which the podocyte is a key player. For example, a current project has generated a mouse model of a familial form of FSGS. To achieve this aim we have cloned and mutagenized the mouse alpha-actinin-4 gene. Alpha-actinin-4 is a structural protein that binds to actin filaments in the podocyte thereby maintaining this epithelial cell's complex morphology. Mutations in the human gene have been linked to the development of a familial form of FSGS. The mutant alpha-actinin-4 binds to actin with higher affinity than does the wild type, thereby giving rise to a gain of function phenotype. We hypothesized and confirmed that the introduction of analogous mutations into the mouse alpha-actinin-4 gene, along with its overexpression in mice under the control of the nephrin promoter would result in an FSGS phenotype. These mice show extensive sclerosis and podocyte foot process fusion, characteristic of an FSGS phenotype. This transgenic line could prove to be an invaluable resource in the study of the progression and treatment of FSGS.

Most Recent Publications

Michaud JL;Hosseini-Abardeh M;Farah K;Kennedy CR;, (2009 Mar), Modulating alpha-actinin-4 dynamics in podocytes, Cell Motility & the Cytoskeleton, Vol.66, Issue 3, 166-178

Sedeek M;Hebert RL;Kennedy CR;Burns KD;Touyz RM;, (2009 Mar), Molecular mechanisms of hypertension: role of Nox family NADPH oxidases. [Review] [80 refs], Current Opinion in Nephrology & Hypertension, Vol.18, Issue 2, 122-127

Stitt-Cavanagh E;MacLeod L;Kennedy C;, (2009), The podocyte in diabetic kidney disease. [Review] [128 refs], Thescientificworldjournal, Vol.9, 1127-1139

Cherney DZI;Scholey JW;Zhou J;Zimpelmann J;Kennedy C;Burns KD;Lai V;Miller JA;, (2009), Endothelial nitric oxide synthase gene polymorphisms and the renal hemodynamic response to L-arginine, Kidney International, Vol.75, Issue 3, 327-332

Sequeira J;Boily G;Bazinet S;Saliba S;He X;Jardine K;Kennedy C;Staines W;Rousseaux C;Mueller R;McBurney MW;, (2008 Oct 1), sirt1-null mice develop an autoimmune-like condition, Experimental Cell Research, Vol.314, Issue 16, 3069-3074

Faour WH;Gomi K;Kennedy CR;, (2008 Nov), PGE(2) induces COX-2 expression in podocytes via the EP(4) receptor through a PKA-independent mechanism, Cellular Signalling, Vol.20, Issue 11, 2156-2164

Michaud JL;Kennedy CR;, (2007 Jun), The podocyte in health and disease: insights from the mouse. [Review] [88 refs], Clinical Science, Vol.112, Issue 6, 325-335

Kennedy CR;Xiong H;Rahal S;Vanderluit J;Slack RS;Zhang Y;Guan Y;Breyer MD;Hebert RL;, (2007 Feb), Urine concentrating defect in prostaglandin EP1-deficient mice, American Journal of Physiology - Renal Physiology, Vol.292, Issue 2, F868