Date of Award

5-2014

Level of Access Assigned by Author

Campus-Only Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Leif Oxburgh

Second Committee Member

Calvin Vary

Third Committee Member

Robert Friesel

Abstract

The kidneys are critical organs in physiology and disease. With chronic kidney disease on the rise around the globe, it is of utmost importance to uncover the mechanisms of kidney fibrosis and glomerulosclerosis in order to devise treatment alternatives to dialysis and organ transplantation. The renal peritubular and mesangial cells are of particular interest as these populations are prone to the hyper proliferation and deleterious ECM deposition resulting in chronic kidney disease (CKD). While cell signaling mediators, notably TGFβ signaling, of CKD are known, the specific intracellular mechanisms of these signals is not fully understood. In this work we examine known and putative TFGβ receptor interacting proteins within the peritubular compartment and glomerulus, elucidate the expression domain and potential gene regulatory roles of Foxd1 in adult kidney cells, and finally delete the key MAPK protein downstream of TGFP with in the Foxd1 lineage of cells. We find that the protein DAPK2 is expressed within the peritubular compartment, and that Foxd1 is expressed in adult podocytes. Conditional deletion of MAP3K7 in the Foxdl lineage of peritubular and mesangial cells results in juvenile nephrosis that resembles the human syndrome Denys- Drash, both in its phenotypic presentation and its responsiveness to the clinically used treatment, Cyclosporin A. Using mouse genetics we identify important tools and disease models that will be valuable in further defining the mechanisms of CKD in humans, and lead to better treatments for this increasingly prevalent condition.

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