Regulation of blood pressure and renal electrolyte balance by Cullin-RING ligases.

Abstract

PURPOSE OF REVIEW:

Efforts to explore the pathogenic mechanisms underlying hereditary hypertension caused by a single gene mutation have brought about conceptual advances in our understanding of blood pressure regulation. We here discuss a novel pathogenic mechanism underlying the hereditary hypertensive disease pseudohypoaldosteronism type II (PHAII), caused by mutations in three different genes encoding for Cullin-3, Kelch-like protein 3 (KLHL3), and with-no-lysine kinases (WNKs).

RECENT FINDINGS:

In 2001, mutations in genes encoding for WNKs were identified as being responsible for PHAII. Recent advancements in genetics, in particular whole-exome sequencing, have revealed that mutations in two additional genes encoding for KLHL3 and Cyllin3 also cause PHAII. This discovery contributed to the clarification of the previously unknown regulatory mechanism of WNKs, namely WNK ubiquitination by the KLHL3-Cullin-3 E3 ligase complex.

SUMMARY:

Levels of WNKs within cells are regulated via ubiquitination by the KLHL3-Cullin-3 E3 ligase complex and are important determinants of the activity of the WNK-oxidative stress-responsive gene 1 and Ste20-related proline-alanine-rich kinase-SLC12A transporter signaling cascade. The PHAII-causing mutations in WNK4, KLHL3, and Cullin-3 result in the decreased ubiquitination and increased abundance of WNK4 in the kidney, thereby activating the thiazide-sensitive NaCl cotransporter and causing PHAII.

• Authors: Shinichi Uchida
• Journal: Current opinion in nephrology and hypertension (Curr Opin Nephrol Hypertens) Vol. 23 Issue 5 Pg. 487-93 (Sep 2014) ISSN: 1473-6543 [Electronic] England
• PMID: 24992566 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Adaptor Proteins, Signal Transducing
• CUL3 protein, human
• Carrier Proteins
• Cullin Proteins
• Intracellular Signaling Peptides and Proteins
• KLHL3 protein, human
• Microfilament Proteins
• Minor Histocompatibility Antigens
• Protein Serine-Threonine Kinases
• WNK Lysine-Deficient Protein Kinase 1
• WNK1 protein, human
• WNK4 protein, human

Topics

• Adaptor Proteins, Signal Transducing
• Animals
• Blood Pressure (genetics)
• Carrier Proteins (metabolism)
• Cullin Proteins (genetics, metabolism)
• Genetic Predisposition to Disease
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Kidney (enzymology, physiopathology)
• Microfilament Proteins
• Minor Histocompatibility Antigens
• Mutation
• Phenotype
• Protein Serine-Threonine Kinases (metabolism)
• Pseudohypoaldosteronism (enzymology, genetics, physiopathology)
• Signal Transduction
• WNK Lysine-Deficient Protein Kinase 1
• Water-Electrolyte Balance (genetics)