Diabetic nephropathy represents the leading cause of end stage renal disease worldwide and requires a kidney transplant or dialysis to survive. The number of patients suffering from diabetes is expected to increase, thus the number of patients with diabetic nephropathy is expected to concomitantly increase. Current treatment for diabetic nephropathy is not sufficient to prevent disease progression in most patients thus there is a need to develop novel therapies to treat diabetic nephropathy.
The earliest changes that occur during the pathogenesis of diabetes occur in the glomerulus. The mesangial cells are a subpopulation of cells in the glomerulus that are responsible for coordinating responses with other nearby cell types. Transforming growth factor (TGF)-β1 is a cytokine that mesangial cells secrete, and has been identified as a profibrotic factor during the pathogenesis of diabetic nephropathy. Concerns have been raised in the use of direct anti-TGF-β1 therapy due to adverse events (such as dyspepsia and diarrhea) and lack of efficacy of anti-TGF-β1 monoclonal antibody LY2382770 in patients with diabetic nephropathy. Thus, therapy aimed at modulating TGF-β1 expression or activity may be efficacious in the treatment of diabetic nephropathy while avoiding potential adverse effects.
The hypothesis of this thesis is that SREBP-1 and cell surface GRP78 are novel regulators of TGF-β1 signaling in mesangial cells. Our first study aims to define a novel pathway by which SREBP-1 regulates TGF-β1 signaling in kidney mesangial cells. Our results indicate that SREBP-1 regulates the expression of the type I TGF-β1 receptor through its secretion in exosomes. Our second study expands on these findings and aims to determine if inhibition of SREBP in vivo with the inhibitor fatostatin may prevent diabetic nephropathy. Our results indicate that treatment with fatostatin does not prevent diabetic nephropathy, but accentuates kidney injury in non-diabetic mice. Preliminary results from our lab have indicated that under diabetic conditions, GRP78 is upregulated at the cell surface and may contribute to the activation of SREBP-1 in an ER-stress dependent mechanism. Our third study thus aims to characterize the expression of cell surface GRP78 in diabetic conditions, and to determine its pathological relevance in the development of diabetic nephropathy. Our results have established novel pathways by which TGF-β1 signaling is regulated in mesangial cells. This will assist in identification of novel therapeutic targets that may be of use in the treatment of diabetic nephropathy. / Thesis / Doctor of Philosophy (PhD) / Diabetic kidney disease is the leading cause of end stage renal disease and represents an important risk factor for mortality. The goal of this thesis is to understand and describe the pathways and mechanisms that contribute to the development of diabetic kidney disease in order to identify novel therapeutic targets. This thesis has identified the protein sterol regulatory element binding protein (SREBP)-1 and the cell surface presentation of another protein, the 78 kDa glucose regulated protein (GRP78), as contributors to diabetic kidney disease. Furthermore, this thesis has demonstrated that anti-SREBP therapy with the drug fatostatin did not prevent diabetic kidney disease. These studies show that while inhibiting SREBP-1 and cell surface GRP78 may be effective in the treatment of diabetic kidney disease, the drug fatostatin should not be used for treatment.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22068 |
| Date | 11 1900 |
| Creators | Van Krieken, Richard |
| Contributors | Krepinsky, Joan, Medical Sciences (Blood and Cardiovascular) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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