Effects of Proximal Tubule Angiotensin II Signaling on Energy Metabolism in the Kidney

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2017-12-12

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Gurley, Susan
Xiang, Zhidan

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Abstract

Chronic kidney disease (CKD) affects over 26 million adults in the United States, thus it is imperative that we deduce more about the pathogenesis of the disease. CKD is generally multi-factorial, and loss of renal function can result from a number of diseases and pathologic processes. For example, propagation of kidney injury and renal fibrosis can result from abnormal regulation of energy metabolism in kidney cells. In renal proximal tubule epithelial cells, a key segment of the nephron, fatty acids are a major fuel source. As the proximal tubule is responsible for the bulk of sodium reabsorption by the kidney, maintaining adequate energy balance is crucial to this function; therefore, alterations in fatty acid oxidation in the renal proximal tubule may lead to renal dysfunction. Our hypothesis is that angiotensin II (Ang II) signaling, a major effector of the powerful renin-angiotensin system (RAS), alters fatty acid oxidation and this becomes exaggerated in states of renal injury such as hypertension and diabetes where the RAS can be dysregulated. Therefore, we sought to explore the metabolic changes linked to Ang II signaling in the renal proximal tubule. Increased levels of Ang II have previously been shown to induce renal fibrosis and hypertension. For our studies, we used a novel mouse line, one lacking AT1a receptors in renal proximal tubule cells (PTKO mice) and expected that the lack of AT1a receptors helps to maintain normal fatty acid oxidation in disease states. To model pathology which might stress the renal proximal tubule cells, we induced two diseases: hypertension, by infusing Ang II via osmotic mini pumps and diabetes, by employing a genetic model of type 1 diabetes, the Akita model. Our major outcome was the assessment of gene expression of several key metabolic pathways, using a quantitative PCR analysis of samples from mouse renal cortex, which is rich in proximal tubules. We aimed to measure genetic biomarkers in the fatty acid oxidation pathway, glucose oxidation pathway, markers of renal injury and fibrosis. These studies demonstrate how two clinically-relevant diseases influence metabolism in the kidney and how leveraging the RAS may lead to solutions against this disruption, and potentially alter CKD progression.

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Jimenez Contreras, Fabian (2017). Effects of Proximal Tubule Angiotensin II Signaling on Energy Metabolism in the Kidney. Honors thesis, Duke University. Retrieved from https://hdl.handle.net/10161/16763.


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