Medicine (Austin & Northern Health) - Theses

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Author: Davies, Matthew R. P. × End date: 2019 × Type: PhD thesis × Subject: obesity ×

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    Mechanisms of altered sodium transport in obesity-related hypertension
    Davies, Matthew R. P. ( 2014)
    As rates of obesity continue to rise, obesity related hypertension (ORH) is becoming an increasing health burden on a global scale. Multiple mechanisms underlie the development of hypertension in obesity but important common end-pathways are vasoconstriction and volume expansion due to enhanced tubular reabsorption of sodium. The mechanisms that lead to obesity-related sodium retention at a tubular level are largely unknown. The effects of high fat diet (HFD) induced obesity on distal tubular sodium transporters were studied at different time points. At 2.5 weeks the key sodium-retaining change identified was increased expression of NCC (the target for thiazide diuretics). In contrast, at 14 weeks, NCC expression had returned to baseline but the activities of NKCC2 (the target for frusemide) and ENaC (the target for amiloride) were increased. The increase in NKCC2 activity was shown to be due to increased activating-phosphorylation. There was a marked increase at S126-NKCC2, which identifies a new role for this site in the regulation of blood pressure. A smaller phosphorylation change at T96/T101 due to increased activity of SPAK/OSR1 was also noted in the cortex. This suggests that different mechanisms underlie the establishment and maintenance of sodium retention in obesity. The energy-sensing kinase AMPK has been implicated as a mediator of several adverse consequences of obesity. AMPK has previously been found to phosphorylate S126-NKCC2 in vitro. AMPK activity was reduced in the renal cortex and in cells of the thick ascending limb after 14 weeks of HFD, making it unlikely AMPK was responsible for phosphorylation change at S126-NKCC2 noted at this time. However, in vitro studies employing activation of AMPK and the WNK/SPAK/OSR1 pathway in wild type and AMPK-null murine embryonic fibroblasts have revealed a role for AMPK in negatively regulating activating-phosphorylation of SPAK/OSR1. This suggests obesity-related AMPK suppression is responsible for the enhanced T96/T101-NKCC2 found in the renal cortex after 14 weeks of HFD through activation of SPAK/OSR1. The widely expressed basolateral sodium potassium 2 chloride co-transporter NKCC1 is closely related to NKCC2 and shares many structural and functional properties. A role for NKCC1 in regulating blood pressure through effects on vascular tone has previously been identified. A role for AMPK in regulating the function of NKCC1 was studied. AMPK was found to negatively regulate NKCC1 activity through inhibiting activating-phosphorylation at T212/217. This was due to reduced activity of SPAK/OSR1; phosphatase activity and surface expression were unchanged by activation of AMPK. In summary, the current study has revealed that different tubular mechanisms are involved in the establishment and maintenance of sodium retention in obesity. Increased phosphorylation of S126-NKCC2 has been identified as a hitherto unrecognized mediator of enhanced sodium reabsorption in ORH. Furthermore, for the first time, obesity-related suppression of AMPK has been linked to activation of SPAK/OSR1. Through downstream effects on NKCC2 and NKCC1, respectively, this links AMPK suppression with sodium retention and vasoconstriction, the key mechanisms that drive the development of ORH.