Year: 2012
Type: article
Abstract: Hypertension, affecting over one billion people worldwide, is one of the leading risk factors for heart attack and stroke.Kidney cross-transplantation studies between hypertensive and normotensive people and strains of rats provide the most compelling evidence for the fundamental role of the kidney in the pathogenesis of hypertension.Recently, there is growing evidence supporting Arthur Guyton's hypothesis that a common characteristic feature of hypertension is impaired renal sodium excretion.However, the exact molecular mechanism responsible for the impaired renal sodium excretion is not clearly defined.The overall aim of this dissertation is to improve our understanding of Na/K-ATPase and sodium proton exchanger 3 (NHE3) trafficking regulation and determine molecular mechanisms of renal proximal tubular sodium iv handling, which might contribute to the impaired sodium excretion associated with hypertension and results may help to develop effective therapy for hypertension.Renal proximal tubules (RPTs) responsible for 65-70% of filtered sodium and water reabsorption have profound effects on renal and body fluid balance associated with hypertension.Studies from our lab were the first to demonstrate that in renal proximal tubular cells, binding of cardiotonic steroids (CTS) such as ouabain to Na/K-ATPase stimulates Na/K-ATPase signaling cascade and induces the redistribution of basolateral Na/K-ATPase and apical NHE3, leading to a net increase in urinary sodium excretion.The first manuscript entitled "Ouabain-stimulated trafficking regulation of the Na/K-ATPase and NHE3 in renal proximal tubule cells" improves our understanding of Na/K-ATPase and NHE3 trafficking regulation.Three renal proximal tubular cell lines (human HK-2, porcine LLC-PK1, and AAC-19 originated from LLC-PK1 cells in which the pig α1 was replaced by ouabainresistant rat α1) were employed to compare ouabain-induced regulation of the α1 subunit and NHE3 as well as transcellular 22 Na + transport.Data indicate that our previous observations that ouabain-induced redistribution of Na/K-ATPase α1 subunit and NHE3 is not species-specific.In LLC-PK1 cells, ouabain also inhibited the endocytic recycling of internalized NHE3, but has no significant effect on recycling of endocytosed α1 subunit.The second manuscript entitled "Impairment of Na/K-ATPase signaling in renal proximal tubule contributes to Dahl salt-sensitive hypertension" defines a Dr. Deepak Malhotra, and Dr. Zijian Xie, for serving on my dissertation committee, for their expert suggestions, contributions and good-natured support throughout the production of my research and dissertation.
Author: Yanling Yan
Institution: University of Toledo
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W634205734