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1 Laboratory of Receptor and Signal Transduction, Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI, USA
2 Department of Physiology, Tulane University Health Sciences Center, New Orleans, LA, USA
3 Laboratory of Receptor and Signal Transduction, Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, MI, USA; Department of Physiology, Wayne State University School of Medicine, Detroit, MI, USA
* To whom correspondence should be addressed. E-mail: jzhuo1{at}hfhs.org.
Long-term angiotensin II (Ang II) administration is associated with increased Ang II accumulation in the kidney, but intrarenal compartment(s) involved in this response remains to be determined. We tested the hypothesis that a) extracellular Ang II is taken up by proximal tubule cells (PTCs) through AT1 receptor-mediated endocytosis, b) this process is regulated by cytoskeleton microtubule- and tyrosine phosphatase-dependent mechanisms, and c) AT1 receptor-mediated endocytosis of Ang II has a functional relevance by modulating intracellular cAMP signaling. In cultured PTCs, ([125I]-Tyr)-Ang II and fluorescein labeled-Ang II were internalized in a time-dependent manner and colocalized with the endosome marker Alexa Fluor 594-transferrin. Endocytosis of extracellular Ang II was inhibited by the AT1 receptor blocker losartan (16.5 ± 4.6%, p < 0.01 vs. Ang II: 78.3 ± 6.2%) and by the tyrosine phosphatase inhibitor phenylarsine oxide (PAO) (30.0 ± 3.5%, p < 0.05 vs. Ang II). Intracellular Ang II levels were increased by ~ 58% (basal: 229.8 ± 11.4 vs. Ang II: 361.3 ± 11.8 pg Ang II/mg protein, p < 0.01), and the responses were blocked by losartan (p < 0.01), the cytoskeleton microtubule inhibitor colchicine (p < 0.05), and PAO (p <0.01), whereas depletion of clathrin-coated pits with hyperosmotic sucrose had no effect (356.1 ± 25.5 pg Ang II/mg protein, n.s.). Ang II accumulation was associated with significant inhibition of both basal (control: 15.5 ± 2.8 vs. Ang II: 9.1 ± 2.4 pmol/mg protein, p < 0.05) and forskolin-stimulated cAMP signaling (forskolin: 68.7 ± 8.6 vs. forskolin+Ang II: 42.8 ± 13.8 pmol/mg protein, p < 0.01). These effects were blocked by losartan and PAO. We conclude that extracellular Ang II is internalized in PTCs through AT1 receptor-mediated endocytosis and that internalized Ang II may play a functional role in proximal tubule cells by inhibiting intracellular cAMP signaling.
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