Endoplasmic reticulum (ER) stress, which results from the aggregation of misfolded proteins in the ER, has been implicated in many forms of kidney injury, including hypertensive nephrosclerosis. ER stress induction increases levels of active TGFβ1, a pro-fibrotic cytokine, which can lead to epithelial-to-mesenchymal transition (EMT) in renal proximal tubular cells. EMT occurs when epithelial cells undergo phenotypic changes, which can be prevented by inhibiting ER stress. Further, the ER stress protein TDAG51 is essential for the development of TGFβ1-mediated fibrosis. The low molecular weight chemical chaperone 4-phenylbutyrate (4-PBA) can protect against ER stress-mediated kidney injury. It acts directly on the kidney, and can prevent ER stress, renal tubular damage, and acute tubular necrosis. In a tunicamycin-mediated model of kidney injury, this damage is prevented primarily through repression of the pro-apoptotic ER stress protein CHOP. Along with providing renoprotective effects, 4-PBA can inhibit endothelial dysfunction and elevated blood pressure in a rat model of essential hypertension. In addition to lowering blood pressure, 4-PBA reduces contractility, augments endothelial-dependent vasodilation, and normalizes media-to-lumen ratio in mesenteric arteries from spontaneously hypertensive rats. Further, ER stress leads to reactive oxygen species generation, which is reduced with 4-PBA. Dahl salt-sensitive rats given 4-PBA are protected from hypertension, proteinuria, albuminuria, and renal pathology. Rats provided with vasodilatory medications demonstrate that lowering blood pressure alone is not renoprotective. In fact, endothelial dysfunction, as demonstrated by an impaired myogenic response, is culpable in the breakdown of the glomerular filtration barrier and subsequent renal damage. As such, alleviating ER stress using 4-PBA serves as a viable therapeutic strategy to preserve renal function and prevent ER stress-mediated endothelial dysfunction, renal fibrosis, glomerular filtration barrier destruction, and progression of hypertensive nephrosclerosis. / Thesis / Doctor of Philosophy (PhD) / Chronic kidney disease is characterized by progressive loss of kidney function, and is a major public health problem. Kidney cells make proteins that help the kidney function properly. However, if the proteins are made improperly, the kidney does not function as well. This can lead to poor filtration and protein in the urine, damage to important kidney structures, and kidney scarring. High blood pressure, a risk factor for kidney disease, is often accused of causing kidney damage. This thesis shows that malfunctioning blood vessels can cause kidney injury, and lowering blood pressure may not prevent this. However, there are pharmacological molecules that can protect the kidney from damage. These molecules help the cells make proteins properly, preventing blood vessel malfunction and kidney damage. Our findings suggest that helping blood vessels and kidney cells create properly functioning proteins is more protective for the kidney than lowering blood pressure alone.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22040 |
| Date | January 2017 |
| Creators | Carlisle, Rachel E. |
| Contributors | Dickhout, Jeffrey G., Medical Sciences (Division of Physiology/Pharmacology) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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