• Childhood kidney disease
• Congenital urinary tract obstruction
  

The mammalian kidney develops along a complex, predetermined pathway, involving numerous iterative processes, and guided by the recruitment of a number of key genes and their protein products. In general, a number of growth factors, including the insulin-like growth factors, are responsible for both early cell events such as kidney cell determination, and later events such as kidney cell differentiation, development, and survival. We have developed several clinically relevant approaches to study abnormal kidney development, including in vitro experimental models, as well as a mouse and a non-human primate model of obstructive nephropathy.

The most important cause of endstage kidney disease and kidney failure in children is urinary tract obstruction during fetal life. The overarching goal of our lab is to apply our knowledge of normal and abnormal kidney development to the improvement of care and outcome of children with fetal urinary tract obstruction. To that end we have developed a number of approaches and experimental models, including in vitro cell systems, and a mouse and non-human primate model of obstructive renal dysplasia. We are presently studying:

1. In vivo models of fetal urinary tract obstruction. In collaboration with our colleagues at UC Davis, and as part of the Center of Excellence in Translational Human Stem Cell Research we have developed and characterized a non human fetal primate model of congenital urinary tract obstruction. This model is a powerful tool to explore some of the more practical issues of in utero therapy as well as providing an accurate representation of the pathogenesis of this important pediatric disease, including the extensive remodeling and phenotypic transformation of the injured fetal tubules. We have also more recently developed a postnatal model of unilateral ureteric obstruction in the mouse in order to study the role of mechanosensation in injury and fibrosis.
2. Signaling events responsible for tubular injury and fibrosis. Using both primary and SV40 transformed mouse inner medullary collecting duct cell lines we induced mesenchymal transition through stimulation with both transforming growth factor beta-1 and insulin-like growth factor-1. This work confirms the in vivo observation of CD mesenchymal transition, and emphasizes an important role for growth factor-mediated early disruption of the collecting duct cell membrane E-cadherin-ß-catenin complexes, and for the regulation of the EMT transcriptome in these cells. Studies are underway to identify important intermediary transcription factors defined in cancer cells which may also play a role in the response of injured renal tubular epithelial cells.
3. Identification and isolation of renal epithelial progenitors. Using gene and protein expression studies we have identified cell-specific CD24 expression during early tubular epithelial cell determination in the developing human fetal kidney. We have successfully isolated and characterized CD24+ cells and determined their progenitor phenotype. Studies are underway to test the potential usefulness of these cells in the repair of injured kidneys during fetal life.

Batchelder CA, Lee CCI, Matsell DG, Yoder MC, Tarantal AF. Renal ontogeny in the rhesus monkey (Macaca mulatta) and directed differentiation of human embryonic stem cells towards kidney precursors. Differentiation, In Press.

Butt MJ, Ivanova L, Toran N, Matsell DG. Remodeling of the fetal collecting duct epithelium. American Journal of Pathology, In Press.

Ivanova L, Butt MJ, Matsell DG: Mesenchymal transition in kidney collecting duct epithelial cells. Am J Physiol Renal Physiol. 294:F1238-48, 2008

Bridgewater DJ, Dionne JM, Butt MJ, Matsell DG: The role of the type I insulin-like growth factor receptor (IGF-IR) in glomerular integrity. Growth Hormone & IGF Research 18: 26-37, 2008

Butt MJ, Tarantal AF, Matsell DG: Collecting duct epithelial mesenchymal transition in a non-human primate model of fetal obstructive nephropathy. Kidney International 72: 936-944, 2007

Garg AX, Clark WF, Salvadori M, Thiessen-Philbrook HR, Matsell D: Absence of renal sequelae after childhood E. coli O157:H7 gastroenteritis. Kidney International 70:807-12, 2006.

Bridgewater DJ, Ho J, Sauro V, Matsell DG: Insulin-like growth factors inhibit podocyte apoptosis through the PI3 kinase pathway. Kidney Intl 67:1308-1314, 2005.

Garg AX, Clark W, Salvadori M, Macnab J, Suri R, Haynes RB, Matsell DG: Microalbuminuria 3 years after recovery from E.coli O157 hemolytic uremic syndrome due to municipal water contamination. Kidney Int 67:1476-1482, 2005.

Garg AX, Suri R, Barrowman N, Rehman F, Matsell D, Rosas-Arellano P, Salvadori M, Haynes RB, Clark WF. The long-term renal prognosis of diarrhea associated hemolytic uremic syndrome: A systematic review, meta-analysis and meta-regression analysis of 3476 children from 49 studies. JAMA 290:1360-70, 2003 .

Bridgewater DJ, Matsell DG. Insulin-like growth factor binding protein-2 modulates podocyte mitogenesis. Pediatr Nephrol 18:1109-15, 2003.

Detweiler Fellowship Award

The Kidney Foundation of Canada Fellowship Award

The Kidney Foundation of Canada Scholarship Award

Michael Butt – PhD student
Larissa Ivanova - Research technician
Dr. Peter Trnka - M.Sc. student
Dr. Cherry Mammen - M.Sc. student
Marc Solomon - Co-op student