caa a22 4500 530045982 CHVBK 20190919033537.0 cr unu---uuuuu 181024e201806 xx s 000 0 eng 10.1681/ASN.2017080826 doi (SERVAL)BIB_A3FC0F6C0BF9 29773687 pmid 000434349100017 isiid The Role of Intercalated Cell Nedd4-2 in BP Regulation, Ion Transport, and Transporter Expression [Elektronische Daten] [M. Nanami, T.D. Pham, Y.H. Kim, B. Yang, R.L. Sutliff, O. Staub, J.D. Klein, K.I. Lopez-Cayuqueo, R. Chambrey, A.Y. Park, X. Wang, V. Pech, J.W. Verlander, S.M. Wall] BackgroundNedd4-2 is an E3 ubiquitin-protein ligase that associates with transport proteins, causing their ubiquitylation, and then internalization and degradation. Previous research has suggested a correlation between Nedd4-2 and BP. In this study, we explored the effect of intercalated cell (IC) Nedd4-2 gene ablation on IC transporter abundance and function and on BP.Methods We generated IC Nedd4-2 knockout mice using Cre-lox technology and produced global pendrin/Nedd4-2 null mice by breeding global Nedd4-2 null (Nedd4-2 -/- ) mice with global pendrin null (Slc26a4 -/- ) mice. Mice ate a diet with 1%-4% NaCl; BP was measured by tail cuff and radiotelemetry. We measured transepithelial transport of Cl - and total CO 2 and transepithelial voltage in cortical collecting ducts perfused in vitro Transporter abundance was detected with immunoblots, immunohistochemistry, and immunogold cytochemistry.Results IC Nedd4-2 gene ablation markedly increased electroneutral Cl - /HCO 3 - exchange in the cortical collecting duct, although benzamil-, thiazide-, and bafilomycin-sensitive ion flux changed very little. IC Nedd4-2 gene ablation did not increase the abundance of type B IC transporters, such as AE4 (Slc4a9), H + -ATPase, barttin, or the Na + -dependent Cl - /HCO 3 - exchanger (Slc4a8). However, IC Nedd4-2 gene ablation increased CIC-5 total protein abundance, apical plasma membrane pendrin abundance, and the ratio of pendrin expression on the apical membrane to the cytoplasm. IC Nedd4-2 gene ablation increased BP by approximately 10 mm Hg. Moreover, pendrin gene ablation eliminated the increase in BP observed in global Nedd4-2 knockout mice.Conclusions IC Nedd4-2 regulates Cl - /HCO 3 - exchange in ICs., Nedd4-2 gene ablation increases BP in part through its action in these cells. Nanami M. aut Pham T.D. aut Kim Y.H. aut Yang B. aut Sutliff R.L. aut Staub O. aut Klein J.D. aut Lopez-Cayuqueo K.I. aut Chambrey R. aut Park A.Y. aut Wang X. aut Pech V. aut Verlander J.W. aut Wall S.M. aut Journal of the American Society of Nephrology 29/6(2018-06), 1706-1719 29:6<1706-1719 2018 29 1 article serval SERVAL 700 1- Nanami M. aut SERVAL 700 1- Pham T.D. aut SERVAL 700 1- Kim Y.H. aut SERVAL 700 1- Yang B. aut SERVAL 700 1- Sutliff R.L. aut SERVAL 700 1- Staub O. aut SERVAL 700 1- Klein J.D. aut SERVAL 700 1- Lopez-Cayuqueo K.I. aut SERVAL 700 1- Chambrey R. aut SERVAL 700 1- Park A.Y. aut SERVAL 700 1- Wang X. aut SERVAL 700 1- Pech V. aut SERVAL 700 1- Verlander J.W. aut SERVAL 700 1- Wall S.M. aut SERVAL 773 0- Journal of the American Society of Nephrology 29/6(2018-06), 1706-1719 29:6<1706-1719 2018 29 BK010053 XK010053 XK010000 SERVAL SERVAL SERVAL article