Abstract
Mendelian hypertension is rare; however, Mendelian syndromes have taught us an amazing amount about mechanisms of distal sodium and chloride reabsorption, as well as how systemic hypertension might come about. In this issue of EMBO Molecular Medicine, Schumacher et al (2015) present a mouse model of the Cullin-3 (CUL3Δ403–459) mutation, which causes a form of pseudohypoaldosteronism type-2 (PHA-2). CUL3 is involved in ubiquitination. Surprising is the severity of the hypertension, which may be explained in part on the basis of CUL3 actions in vascular cells. The findings underscore the role of “cleanup” in the maintenance of normal physiology.
Highlights
Mendelian hypertension is rare; Mendelian syndromes have taught us an amazing amount about mechanisms of distal sodium and chloride reabsorption, as well as how systemic hypertension might come about
The authors suggested that CUL3 and the BTB-domain-containing Kelch-like 3 (KLHL3) proteins are components of cullin-really interesting new gene (RING) E3 ligase complexes that ubiquitinate substrates bound to Kelch propeller domains (Boyden et al, 2012)
Ohta et al subsequently immunoprecipitated KLHL3 and found that KLHL3 was strongly associated with WNK isoforms and CUL3, but not with other components of the pathway regulating NCC (Ohta et al, 2013)
Summary
Mendelian hypertension is rare; Mendelian syndromes have taught us an amazing amount about mechanisms of distal sodium and chloride reabsorption, as well as how systemic hypertension might come about. The authors suggested that CUL3 and the BTB-domain-containing KLHL3 proteins are components of cullin-really interesting new gene (RING) E3 ligase complexes that ubiquitinate substrates bound to Kelch propeller domains (Boyden et al, 2012). Their results suggested that the CUL3-KLHL3 E3 ligase complex regulates blood pressure via interaction with, and ubiquitination of WNK isoforms.
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