| First Author | Nanami M | Year | 2018 |
| Journal | J Am Soc Nephrol | Volume | 29 |
| Issue | 6 | Pages | 1706-1719 |
| PubMed ID | 29773687 | Mgi Jnum | J:286202 |
| Mgi Id | MGI:6402339 | Doi | 10.1681/ASN.2017080826 |
| Citation | Nanami M, et al. (2018) The Role of Intercalated Cell Nedd4-2 in BP Regulation, Ion Transport, and Transporter Expression. J Am Soc Nephrol 29(6):1706-1719 |
| abstractText | 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 CO2 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(-)/HCO3(-) 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(-)/HCO3(-) 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(-)/HCO3(-) exchange in ICs., Nedd4-2 gene ablation increases BP in part through its action in these cells. |
