An isoform of Nedd4-2 is critically involved in the renal adaptation to high salt intake in mice

Minegishi, Shintaro; Ishigami, Tomoaki; Kino, Tabito; Chen, Lin; Nakashima-Sasaki, Rie; Araki, Naomi; Yatsu, Keisuke; Fujita, Megumi; Umemura, Satoshi

doi:10.1038/srep27137

Cited by 18 publications

(27 citation statements)

References 36 publications

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“…The Nedd4-2 C2 domain is encoded by exon 2 in chromosome 18 of mice, and Nedd4-2 C2 KO mice show salt-sensitive hypertension under high oral salt intake, as reported previously [21]. There were no significant differences between the body weights of Nedd4-2 C2 KO mice and their WT (wild type) littermates, as shown in Table 1.…”

Section: Resultssupporting

confidence: 80%

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

Kino

Ishigami

Murata

et al. 2017

IJMS

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The epithelial sodium channel (ENaC) plays critical roles in maintaining fluid and electrolyte homeostasis and is located in the aldosterone-sensitive distal nephron (ASDN). We previously found that Nedd4-2 C2 knockout (KO) mice showed salt-sensitive hypertension with paradoxically enhanced ENaC gene expression in ASDN under high oral salt intake. Eplerenone (EPL), a selective aldosterone blocker, is a promising therapeutic option for resistant or/and salt-sensitive hypertension. We examined the effect of EPL on Nedd4-2 C2 KO mice with respect to blood pressure, metabolic parameters, and molecular level changes in ASDN under high oral salt intake. We found that EPL failed to reduce blood pressure in KO mice with high oral salt intake and upregulated ENaC expression in ASDN. Thus, salt-sensitive hypertension in Nedd4-2 C2 KO was EPL-resistant. Gene expression analyses of laser-captured specimens in ASDN suggested the presence of non-aldosterone-dependent activation of ENaC transcription in ASDN of Nedd4-2 C2 KO mice, which was abolished by amiloride treatment. Our results from Nedd4-2 C2 KO mice suggest that enhanced ENaC gene expression is critically involved in salt-sensitive hypertension under certain conditions of specific enzyme isoforms for their ubiquitination.

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Section: Resultssupporting

confidence: 80%

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

Kino

Ishigami

Murata

et al. 2017

IJMS

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“…In our study, we observed that NEDD4L-dC2 was more potent at ubiquitinating CRTC3 than the form of NEDD4L containing the C2 domain, suggesting that different tissue types may possess double feedback regulation mechanisms to ensure that CRTC3 signaling is turned off. Recently, NEDD4L C2 domain-specific knockout mice have been generated (35). Because NEDD4L-dC2 was more active in ubiquitinating CRTC3, it would be interesting to investigate whether CRTC3 protein levels and lipid metabolism are elevated in these mice.…”

Section: Discussionmentioning

confidence: 99%

NEDD4L limits cAMP signaling through ubiquitination of CREB‐regulated transcription coactivator 3

et al. 2018

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The transcription factor cAMP-responsive element-binding protein (CREB) is involved in a variety of physiologic processes. Although its activity appears to be largely correlated with its phosphorylation status, cAMP-mediated dephosphorylation and the subsequent nuclear migration of the CREB-regulated transcription factors (CRTCs) are required to stimulate CREB transcriptional activity. Among the 3 identified mammalian homologs of CRTCs, CRTC3 has been shown to be expressed predominantly in adipose tissues in response to catecholamine signals that regulate lipid metabolism. Here, we show that prolonged cAMP signaling down-regulates CRTC3 in a proteasome-dependent manner and that neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L), a specific ubiquitin ligase for CRTC3, is responsible for this process. By recognizing the PY motif of CRTC3, NEDD4L interacts with CRTC3 and promotes its polyubiquitination. Interaction between NEDD4L and CRTC3 is further boosted by cAMP signaling, and this enhanced interaction appears to be dependent on the cAMP-mediated phosphorylation of NEDD4L at the Ser448 site. Furthermore, we show that food withdrawal stimulates NEDD4L phosphorylation in mice, which then show a decrease of adipose tissue CRTC3 protein levels. Together, these results suggest that NEDD4L plays a key role in the feedback regulation of cAMP signaling by limiting CRTC3 protein levels.-Kim, Y.-H., Yoo, H., Hong, A.-R., Kwon, M., Kang, S.-W., Kim, K., Song, Y. NEDD4L limits cAMP signaling through ubiquitination of CREB-regulated transcription coactivator 3.

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“…Numerous prior reports have shown that NEDD4-2 interacts with and ubiquitylates ENaC, reducing channel cell surface expression. [24][25][26]28,32,53,54 The physiologic relevance of ENaC/NEDD4-2 interactions has largely been explored within the context of Liddle syndrome or signaling pathways that block NEDD4-2 activity. However, a rationale explaining why NEDD4-2 was selected during evolution to tonically inhibit ENaC activity when aldosterone levels are low has been lacking.…”

Section: Discussionmentioning

confidence: 99%

“…Although NEDD4-2 is best characterized as an ENaC inhibitor, [24][25][26][27][28][29][30][31][32] it was recently shown that its role is more complex. Both in vitro, as well as in NEDD4-2 knockout (Nedd4L Pax8/LC1 ) mice given a high Na + diet (HSD), NEDD4-2 acts as a NCC inhibitor, 20,21 whereas it affects ENaC to a lesser degree.…”

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confidence: 99%

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

Al‐Qusairi

Basquin

Roy

et al. 2017

JASN

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Adaptation of the organism to potassium (K) deficiency requires precise coordination among organs involved in K homeostasis, including muscle, liver, and kidney. How the latter performs functional and molecular changes to ensure K retention is not well understood. Here, we investigated the role of ubiquitin-protein ligase NEDD4-2, which negatively regulates the epithelial sodium channel (ENaC), Na/Cl cotransporter (NCC), and with no-lysine-kinase 1 (WNK1). After dietary K restriction for 2 weeks, compared with control littermates, inducible renal tubular NEDD4-2 knockout ( ) mice exhibited severe hypokalemia and urinary K wasting. Notably, expression of the ROMK K channel did not change in the distal convoluted tubule and decreased slightly in the cortical/medullary collecting duct, whereas BK channel abundance increased in principal cells of the connecting tubule/collecting ducts. However, K restriction also enhanced ENaC expression in mice, and treatment with the ENaC inhibitor, benzamil, reversed excessive K wasting. Moreover, K restriction increased WNK1 and WNK4 expression and enhanced SPAK-mediated NCC phosphorylation in mice, with no change in total NCC. We propose a mechanism in which NEDD4-2 deficiency exacerbates hypokalemia during dietary K restriction primarily through direct upregulation of ENaC, whereas increased BK channel expression has a less significant role. These changes outweigh the compensatory antikaliuretic effects of diminished ROMK expression, increased NCC phosphorylation, and enhanced WNK pathway activity in the distal convoluted tubule. Thus, NEDD4-2 has a crucial role in K conservation through direct and indirect effects on ENaC, distal nephron K channels, and WNK signaling.

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An isoform of Nedd4-2 is critically involved in the renal adaptation to high salt intake in mice

Cited by 18 publications

References 36 publications

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

Eplerenone-Resistant Salt-Sensitive Hypertension in Nedd4-2 C2 KO Mice

NEDD4L limits cAMP signaling through ubiquitination of CREB‐regulated transcription coactivator 3

Renal Tubular Ubiquitin-Protein Ligase NEDD4-2 Is Required for Renal Adaptation during Long-Term Potassium Depletion

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