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PURPOSE OF REVIEW: NEDD4-2 is an ubiquitin-protein ligase that was originally identified as an interactor of the epithelial Na+ channel (ENaC); this interaction is defective in Liddle's syndrome, causing elevated ENaC activity and salt-sensitive hypertension. In this review we aim to highlight progress achieved in recent years demonstrating that NEDD4-2 is involved in the control of Na+ transporters that are different from ENaC, but which also play a role in salt-sensitive hypertension. RECENT FINDINGS: It has been shown that NEDD4-2 interacts with ubiquitylates and negatively regulates the thiazide-sensitive NCC (Na+,Cl- -cotransporter), both in vitro and in vivo in inducible, nephron-specific Nedd4-2 knockout mice. Moreover, evidence has been provided that NEDD4-2 is also involved in the regulation of human NHE3 (Na+,H+-exchanger 3) and NKCC2 (Na+,K+,2Cl- -cotransporter 2). SUMMARY: The emerging role of NEDD4-2 in the regulation of different Na+ transporters along the nephron and the identification of human polymorphisms in the NEDD4-2 gene (Nedd4L) related to salt-sensitive hypertension makes this ubiquitin-protein ligase an interesting target for the development of antihypertensive drugs.

Ubiquitylation is crucial for regulating numerous cellular functions. In the kidney, ubiquitylation regulates the epithelial Na(+) channel ENaC. The importance of this process is highlighted in Liddle's syndrome, where mutations interfere with ENaC ubiquitylation, resulting in constitutive Na(+) reabsorption and hypertension. There is emerging evidence that NCC, involved in hypertensive diseases, is also regulated by ubiquitylation. Here, we discuss the current knowledge and recent findings in this field.

The kidneys play a major role in Na + homeostasis and consequently in blood volume and pressure regulation. This is highlighted by the genetic linkage of numerous genetic diseases causing either salt-sensitive hypoor hypertension to mutations affecting the regulation of ion transporters or channels in the kidney (e.g. Liddle''s, Familial Hyperkalemic Hypertension (FHHt), or Gitelman’s syndrome). It is also well established that ubiquitylation (i.e. the post-translational modification of proteins with ubiquitin-polypeptides) is crucially involved in these processes. As an example, the intrinsic activity and cell surface expression of the epithelial Na + channel ENaC is negatively regulated by the ubiquitin-protein ligase NEDD4-2. In Liddle''s syndrome, characterized by hypertension, hypokalemic metabolic alkalosis and elevated ENaC activity, the regulation by NEDD4-2 is impaired by mutations on ENaC that inactivate the interaction site with ENaC. Recently, we have shown both in vitro and in vivo that NEDD4-2 is also involved in the control of the thiazide-sensitive Na +,Cl –-cotransporter NCC. Indeed, NEDD4-2 co-immunoprecipitates with NCC induces its ubiquitylation and downregulates NCC at the cell surface in vitro. Moreover, in inducible, nephron-specific NEDD4-2 KO mice NCC is strongly upregulated. It has been shown that NEDD4-2 is regulated by kinases such as the aldosterone-induced SGK1 kinase, or the WNK kinases. Certain kindred of FHHt, characterized by hypertension, hyperkalemia and metabolic acidosis and increased NCC activity, are linked to mutations in KLHL3 or CULLIN3, two subunits of ubiquitin-protein ligase complex, further highlighting the importance of the ubiquitin system in salt regulation and blood pressure control. We will discuss recent progress in the understanding of the role of ubiquitin in this field.

In this review, we discuss genetic evidence supporting Guyton's hypothesis stating that blood pressure control is critically depending on fluid handling by the kidney. The review is focused on the genetic dissection of sodium and potassium transport in the distal nephron and the collecting duct that are the most important sites for the control of sodium and potassium balance by aldosterone and angiotensin II. Thanks to the study of Mendelian forms of hypertension and their corresponding transgenic mouse models, three main classes of diuretic receptors (furosemide, thiazide, amiloride) and the main components of the aldosterone- and angiotensin-dependent signaling pathways were molecularly identified over the past 20years. This will allow to design rational strategies for the treatment of hypertension and for the development of the next generation of diuretics.

Nedd4-2 is a ubiquitin ligase previously demonstrated to regulate endocytosis and lysosomal degradation of the epithelial Na(+) channel (ENaC) and other ion channels and transporters. Recent studies using Nedd4-2 knockout mice specifically in kidney or lung epithelia has revealed a critical role for this E3 ubiquitin ligase in regulating salt and fluid transport in these tissues/organs and in maintaining homeostasis of body blood pressure. Interestingly, the primary targets for Nedd4-2 may differ in these two organs: in the lung Nedd4-2 targets ENaC, and loss of Nedd4-2 leads to excessive ENaC function and to cystic fibrosis - like lung disease, whereas in the kidney, Nedd4-2 targets the Na(+)/Cl(-) cotransporter (NCC) in addition to targeting ENaC. In accord, loss of Nedd4-2 in the distal nephron leads to increased NCC abundance and function. The aldosterone-responsive kinase, Sgk1, appears to be involved in the regulation of NCC by Nedd4-2 in the kidney, similar to its regulation of ENaC. Collectively, these new findings underscore the physiological importance of Nedd4-2 in regulating epithelial salt and fluid transport and balance.

Ion channels and transporters play a critical role in ion and fluid homeostasis and thus in normal animal physiology and pathology. Tight regulation of these transmembrane proteins is therefore essential. In recent years, many studies have focused their attention on the role of the ubiquitin system in regulating ion channels and transporters, initialed by the discoveries of the role of this system in processing of Cystic Fibrosis Transmembrane Regulator (CFTR), and in regulating endocytosis of the epithelial Na(+) channel (ENaC) by the Nedd4 family of ubiquitin ligases (mainly Nedd4-2). In this review, we discuss the role of the ubiquitin system in ER Associated Degradation (ERAD) of ion channels, and in the regulation of endocytosis and lysosomal sorting of ion channels and transporters, focusing primarily in mammalian cells. We also briefly discuss the role of ubiquitin like molecules (such as SUMO) in such regulation, for which much less is known so far.

In the design for a miniature antenna, one looks for the best compromise between volume, bandwidth and efficiency. This best compromise is usually obtained when most of the allotted volume participates in the radiation. We present an antenna which was designed for a mobile communication application integrated in a very small cylindrical volume. The allotted space for the antenna was very small in terms of wavelengths, and the approach chosen was to use a volume as large as possible, thus to make the casing participate in the radiation. The antenna is presented together with its radiation performance.