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1 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
* To whom correspondence should be addressed. E-mail: jzhuo1{at}hfhs.org.
Intracellular angiotensin II (Ang II) induces biological effects in non-renal cells, but it is not known whether it plays a physiological role in renal proximal tubule cells (PTCs). PTCs express angiotensinogen, renin and angiotensin-converting enzyme mRNAs suggesting the presence of high levels of intracellular Ang II, We determine if microinjection of Ang II directly into single PTCs increases intracellular calcium ([Ca2+]i), and, if so, to elucidate the cellular mechanisms involved. Changes in [Ca2+]i responses were studied by fluorescence imaging using the Ca2+ indicator Fluo-3. Ang II (1 nM) was microinjected directly into the cells, while cell surface AT1 receptors were blocked by losartan (10 µM). When Ang II (1 nM) was added to the perfusate, there was a marked increase in [Ca2+]i that was blocked by extracellular losartan. With losartan in the perfusate, intracellular microinjection of Ang II elicited a robust increase in cytoplasmic [Ca2+]i that peaked at 30 seconds (basal: 2.2 ± 0.3 vs. Ang II: 14.9 ± 0.4 relative fluorescence units; p < 0.01). Chelation of extracellular Ca2+ with EGTA (2 mM) did not alter microinjected Ang II-induced [Ca2+]i responses (Ca2+-free+Ang II: 12.3 ± 2.6 relative fluorescence units, n.s. vs. Ang II); however, pretreatment with thapsigargin to deplete intracellular Ca2+ stores or with U73122 to inhibit phospholipase C (1 µM each) markedly attenuated microinjected Ang II-induced [Ca2+]i responses. Combined microinjection of Ang II and losartan abolished [Ca2+]i responses, whereas a combination of Ang II and PD 123319 had no effect. These data demonstrate for the first time that direct microinjection of Ang II into single PTCs increases [Ca2+]i by stimulating intracellular AT1 receptors and releasing Ca2+ from intracellular stores, and suggest that intracellular Ang II may play a physiological role in proximal tubule cell function.
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