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ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3?403-459 mutation.

ABSTRACT: Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion of exon 9 from CUL3 (affecting residues 403-459, CUL3(?403-459)) causes a severe form of FHHt (PHA2E) that is recapitulated closely in a knock-in mouse model. The loss of functionality of CUL3(?403-459) and secondary accumulation of WNK kinases causes substantial NCC activation. This accounts for the hypertension in FHHt but the origin of the hyperkalemia is less clear. Hence, we explored the impact of CUL3(?403-459) on expression of the distal secretory K channel, ROMK, both in vitro and in vivo. We found that expressing wild-type but not the CUL3(?403-459) mutant form of CUL3 prevented the suppression of ROMK currents by WNK4 expressed in Xenopus oocytes. The mutant CUL3 protein was also unable to affect ROMK-EGFP protein expression at the surface of mouse M-1 cortical collecting duct (CCD) cells. The effects of CUL3 on ROMK expression in both oocytes and M-1 CCD cells was reduced by addition of the neddylation inhibitor, MLN4924. This confirms that neddylation is important for CUL3 activity. Nevertheless, in our knock-in mouse model expressing CUL3(?403-459) we could not show any alteration in ROMK expression by either western blotting whole kidney lysates or confocal microscopy of kidney sections. This suggests that the hyperkalemia in our knock-in mouse and human PHA2E subjects with the CUL3(?403-459) mutation is not caused by reduced ROMK expression in the distal nephron.

SUBMITTER: Murthy M

PROVIDER: S-EPMC4945836 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation.

Murthy Meena M Kurz Thimo T O'Shaughnessy Kevin M KM

Physiological reports 20160701 13

Familial hyperkalemic hypertension (FHHt) is a rare inherited form of salt-dependent hypertension caused by mutations in proteins that regulate the renal Na(+)-Cl(-) cotransporter NCC Mutations in four genes have been reported to cause FHHt including CUL3 (Cullin3) that encodes a component of a RING E3 ligase. Cullin-3 binds to WNK kinase-bound KLHL3 (the substrate recognition subunit of the ubiquitin ligase complex) to promote ubiquitination and proteasomal degradation of WNK kinases. Deletion ...[more]

PMID: 27378813

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Project description:BackgroundExercise self-efficacy is a crucial aspect of adopting and maintaining a physically active lifestyle. Regular physical activity may enhance exercise self-efficacy. This study aimed to investigate the baseline associations of physical fitness, physical activity, and body composition with exercise self-efficacy and the effects of military service on exercise self-efficacy. Methods: The sample consisted of healthy young Finnish conscripts (n = 243) undergoing military service. The participants were divided into two groups: an intervention group undergoing a high-intensity functional training program (n = 113) and a control group undergoing traditional physical training within their military service (n = 130). Exercise self-efficacy (adoption and barrier) and aerobic and muscular fitness were measured thrice (baseline, month 3, and month 5). Self-reported leisure-time physical activity and measured fat percentage were collected at baseline.ResultsAdoption and barrier exercise self-efficacy correlated positively with aerobic and muscular fitness and leisure time physical activity (r = 0.33-0.59, p < 0.001), and barrier self-efficacy negatively with fat percentage (r = -0.15, p < 0.05) at baseline. No changes in adoption (time p = 0.912) and barrier self-efficacy (time p = 0.441) occurred during the military service. There were no differences between groups in these changes (group × time interaction p = 0.643 for adoption self-efficacy and p = 0.872 for barrier self-efficacy). Change in muscular fitness correlated positively with change in barrier self-efficacy in the high-intensity functional training group (r = 0.35, p < 0.05). Conclusions: Exercise self-efficacy is positively associated with physical fitness and physical activity among young males. However, military service, whether it involves high-intensity functional physical training or more diverse traditional physical training, does not improve exercise self-efficacy.

Dataset Information

ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3?403-459 mutation.

Publications

ROMK expression remains unaltered in a mouse model of familial hyperkalemic hypertension caused by the CUL3Δ403-459 mutation.

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