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1 Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan, United States
2 Hypertension and Vascular Division, Henry Ford Hospital, 2799 West Grand Blvd, Detroit, Michigan, 48202, United States; Department of Physiology, Wayne State University School of Medicine, 5374 Scott Hall, Detroit, Michigan, 48202, United States
* To whom correspondence should be addressed. E-mail: jzhuo1{at}hfhs.org.
Receptor-mediated endocytosis of angiotensin II (Ang II) plays an important role in the regulation of proximal tubule (PTC) function. Using immortalized rabbit PTCs as a cell model, we tested the hypothesis that extracellular Ang II is taken up by PTCs through AT1 (or AT1a) receptor-mediated endocytosis and that inhibition of Ang II endocytosis using a selective AT1 receptor siRNA (AT1R siRNA) exerts a physiological effect on NHE-3 expression. Western blots and cell imaging with FITC-labeled Ang II confirmed that AT1R siRNA (AT1R siRNA) selectively knocked down AT1 receptors in a time-dependent manner (p < 0.01), whereas a scrambled siRNA had little effect. In non-transfected PTCs, exposure to Ang II (1 nM) for 60 min at 37°C increased intracellular Ang II by 67% (p < 0.01), and induced mitogen-activated protein kinase ERK 1/2 phosphorylation by 63% (p < 0.01). AT1R siRNA reduced Ang II endocytosis to a level similar to losartan, which blocks cell surface AT1 receptors (p < 0.05 vs. Ang II), or to colchicine, which disrupts cytoskeleton microtubules (p < 0.05 vs. Ang II). AT1R siRNA, losartan, and colchicine all attenuated Ang II-induced ERK1/2 activation and cell lysate and apical membrane NHE-3 abundance. The scrambled siRNA had no effect on Ang II endocytosis, ERK1/2 activation or NHE-3 expression. These results suggest that AT1 receptor-mediated endocytosis of extracellular Ang II may regulate proximal tubule sodium transport by increasing total and apical NHE-3 proteins.
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