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Intracellular ANG II induces cytosolic Ca²⁺ mobilization by stimulating intracellular AT₁ receptors in proximal tubule cells

¹Division of Hypertension and Vascular Research, Henry Ford Hospital, Detroit, Michigan; and ²Department of Physiology, Tulane University Health Sciences Center, New Orleans, Louisiana

Submitted 1 July 2005 ; accepted in final form 19 December 2005

Intracellular ANG II induces biological effects in nonrenal 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 determined if microinjection of ANG II directly in single PTCs increases intracellular calcium concentration ([Ca²⁺]_i) and, if so, elucidated 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 in the cells, whereas cell-surface angiotensin type 1 (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 s (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, not significant vs. ANG II); however, pretreatment with thapsigargin to deplete intracellular Ca²⁺ stores or with U-73122 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 in single PTCs increases [Ca²⁺]_i by stimulating intracellular AT₁ receptors and releases Ca²⁺ from intracellular stores, suggesting that intracellular ANG II may play a physiological role in PTC function.

intracellular calcium; kidney; microinjection; proximal tubules; receptor-mediated endocytosis

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