Effect of angiotensin II on the WNK-OSR1/SPAK-NCC phosphorylation cascade in cultured mpkDCT cells and in vivo mouse kidney |
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Authors: | Gulibaha Talati Tatemitsu Rai Shotaro Naito Sei Sasaki |
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Institution: | a Department of Nephrology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima Bunkyo, Tokyo 113-8519, Japan b INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris 7 - Denis Diderot, site Bichat, BP 416, F-75018 Paris, France |
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Abstract: | In our recent study using Wnk4D561A/+ knockin mice, we determined that the WNK-OSR1/SPAK-NaCl cotransporter (NCC) phosphorylation cascade is important for regulating NCC function in vivo. Phosphorylation of NCC was necessary for its plasma membrane localization. Previously, angiotensin II infusion was shown to increase apical membrane expression of NCC in rats. Therefore, we investigated whether angiotensin II was an upstream regulator for the WNK-OSR1/SPAK-NCC cascade in cultured cells and in vivo kidney. In mpkDCT cells, the phosphorylation of OSR1 and NCC was increased 30 min after the addition of angiotensin II (10-9-10−7 M) but returned to baseline after 18 h. In mice, a 5-min infusion of angiotensin II (5 ng/g/min) increased NCC phosphorylation in the kidney at 30 min and 2 h after the injection but returned to baseline 24 h later. This increase was inhibited by angiotensin II receptor blocker (valsartan) but not by aldosterone receptor blocker (eplerenone). Ten-day infusions of angiotensin II (720 ng/day) also increased phosphorylation of OSR1 and NCC in the mouse kidney, and both valsartan and eplerenone inhibited the increased phosphorylation. Although angiotensin II is identified as an upstream regulator for the WNK-OSR1/SPAK-NCC cascade in vivo, aldosterone appears to be the major regulator of this signal cascade in the long-term regulation by angiotensin II. |
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Keywords: | WNK kinase Angiotensin II NaCl cotransporter Kidney Aldosterone blocker |
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