Abstract | BACKGROUND: Activation of RhoA/ Rho kinase (ROK) pathway by angiotensin II (Ang II) is involved in the pathophysiology of hypertension and remodeling. In Bartter's and Gitelman's syndrome (BS/GS), the short-term and long-term signaling of Ang II are blunted. The BS/GS have also reduced expression and response on Ang II challenge of ROK, which indicate downregulation of RhoA/ROK pathway. As causes for RhoA/ROK downregulation in BS/GS, we hypothesized an alteration at the level of the upstream regulators of RhoA such as reduced expression of Rho guanine nucleotide exchange factor ( RhoGEF), which links activation of G protein-coupled receptors to RhoA/ROK signaling or increased guanine nucleotide dissociation inhibitor ( RhoGDI), which inhibits dissociation of GDP from GDI maintaining RhoA in an inactive state. METHODS: In mononuclear cells of 9 BS/GS and 9 healthy controls (C), we looked at gene and protein expression ( reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot) of RhoA, RhoGEF, and RhoGDI. RESULTS: CONCLUSIONS: Reduced p115RhoGEF may explain the downregulation of RhoA/ROK pathway in BS/GS. This is the first report of upstream regulators of RhoA level in BS/GS, a human clinical condition characterized by reduced vascular tone regulation. Because BS/GS represent the mirror image of derangements involved in hypertension, the reduced RhoGEF expression in BS/GS underlines a major impact of RhoA/ROK pathway on blood pressure regulation and confirms BS/GS as a good human model for exploring mechanisms involved in the pathophysiology of hypertension and remodeling.
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Authors | Elisa Pagnin, Andrea Semplicini, Michelangelo Sartori, Achille C Pessina, Lorenzo A Calò |
Journal | American journal of hypertension
(Am J Hypertens)
Vol. 18
Issue 9 Pt 1
Pg. 1200-5
(Sep 2005)
ISSN: 0895-7061 [Print] United States |
PMID | 16182110
(Publication Type: Comparative Study, Journal Article)
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Chemical References |
- Guanine Nucleotide Exchange Factors
- RNA, Messenger
- Receptors, Drug
- Rho Guanine Nucleotide Exchange Factors
- SLC12A3 protein, human
- Solute Carrier Family 12, Member 3
- Symporters
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Topics |
- Adult
- Bartter Syndrome
(genetics, metabolism)
- Blotting, Western
- Female
- Gene Expression
- Guanine Nucleotide Exchange Factors
(genetics, metabolism)
- Humans
- Hypertension
(physiopathology)
- Leukocytes, Mononuclear
(metabolism)
- Male
- Middle Aged
- Mutation
- RNA, Messenger
(genetics, metabolism)
- Receptors, Drug
(genetics)
- Reverse Transcriptase Polymerase Chain Reaction
- Rho Guanine Nucleotide Exchange Factors
- Solute Carrier Family 12, Member 3
- Symporters
(genetics)
- Syndrome
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