We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions.

Activation of tissue renin–angiotensin system (RAS), mainly mediated by an angiotensin II (Ang II) type 1 receptor (AT1R), plays an important role in the development of obesity-related metabolic disorders. We have shown that AT1R-associated protein (ATRAP), a specific binding protein of AT1R, functions as an endogenous inhibitor to prevent excessive activation of tissue RAS. In the present study, we newly generated ATRAP/Agtrap-floxed (ATRAP^fl/fl) mice and adipose tissue-specific ATRAP downregulated (ATRAP^adipoq) mice by the Cre/loxP system using Adipoq-Cre. Using these mice, we examined the functional role of adipose ATRAP in the pathogenesis of obesity-related metabolic disorders. Compared with ATRAP^fl/fl mice, ATRAP^adipoq mice exhibited a decreased ATRAP expression in visceral white adipose tissue (WAT) and brown adipose tissue (BAT) by approximately 30% and 85%, respectively. When mice were fed a high-fat diet, ATRAP^fl/fl mice showed decreased endogenous ATRAP expression in WAT that was equivalent to ATRAP^adipoq mice, and there was no difference in the exacerbation of dietary obesity and glucose and lipid metabolism. These results indicate that ATRAP in BAT does not influence the pathogenesis of dietary obesity or metabolic disorders. Future studies that modulate ATRAP in WAT are necessary to assess its in vivo functions in the development of obesity-related metabolic disorders.