Gene/Protein
Disease
Symptom
Drug
Enzyme
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Target Concepts:
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Query: UNIPROT:P01185 (
vasopressin
)
23,126
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Stimulation of renal collecting duct principal cells with
antidiuretic hormone
(
arginine-vasopressin
, AVP) results in inhibition of the small GTPase
RhoA
and the enrichment of the water channel aquaporin-2 (AQP2) in the plasma membrane. The membrane insertion facilitates water reabsorption from primary urine and fine-tuning of body water homeostasis. Rho guanine nucleotide exchange factors (GEFs) interact with
RhoA
, catalyze the exchange of GDP for GTP and thereby activate the GTPase. However, GEFs involved in the control of AQP2 in renal principal cells are unknown. The A-kinase anchoring protein, AKAP-Lbc, possesses GEF activity, specifically activates
RhoA
, and is expressed in primary renal inner medullary collecting duct principal (IMCD) cells. Through screening of 18,431 small molecules and synthesis of a focused library around one of the hits, we identified an inhibitor of the interaction of AKAP-Lbc and
RhoA
. This molecule, Scaff10-8, bound to
RhoA
, inhibited the AKAP-Lbc-mediated
RhoA
activation but did not interfere with
RhoA
activation through other GEFs or activities of other members of the Rho family of small GTPases, Rac1 and Cdc42. Scaff10-8 promoted the redistribution of AQP2 from intracellular vesicles to the periphery of IMCD cells. Thus, our data demonstrate an involvement of AKAP-Lbc-mediated
RhoA
activation in the control of AQP2 trafficking.
...
PMID:An AKAP-Lbc-RhoA interaction inhibitor promotes the translocation of aquaporin-2 to the plasma membrane of renal collecting duct principal cells. 2937 79
Sepsis and septic shock are among the most common causes of death in the intensive care unit; advanced therapeutic approaches are thus urgently needed. Vascular hyperpermeability represents a major manifestation of severe sepsis and is responsible for the ensuing organ dysfunction and failure. Vasopressin V
1A
receptor (V
1A
R) agonists have shown promise in the treatment of sepsis, increasing blood pressure, and reducing vascular hyperpermeability. The effects of the selective V
1A
R-selective agonist selepressin have been investigated in an in vitro model of thrombin-, vascular endothelial growth factor-, angiopoietin 2-, and lipopolysaccharide (LPS)-induced pulmonary microvascular endothelial hyperpermeability. Results suggest that selepressin counteracts the effects of all four endothelial barrier disruptors in a concentration-dependent manner, as reflected in real-time measurements of vascular permeability by means of transendothelial electrical resistance. Further, selepressin protected the barrier integrity against the LPS-mediated corruption of the endothelial monolayer integrity, as captured by VE-cadherin and actin staining. The protective effects of selepressin were abolished by silencing of the
vasopressin
V
1A
R, as well as by atosiban, an antagonist of the human V
1A
R. p53 appears to be involved in mediating these palliative effects, since selepressin strongly induced its expression levels, suppressed the inflammatory
RhoA
/myosin light chain2 pathway, and triggered the barrier-protective effects of the GTPase Rac1. We conclude that V
1A
R-selective agonists, such as selepressin, may prove useful in the improvement of endothelial barrier function in the management of severe sepsis. SIGNIFICANCE STATEMENT: A cardinal sign of sepsis, a serious disease with significant mortality and no specific treatment, is pulmonary endothelial barrier dysfunction that leads to pulmonary edema. Here, we present evidence that in cultured human lung microvascular endothelial cells, the synthetic, selective
vasopressin
V
1A
receptor agonist selepressin protects against endothelial barrier dysfunction caused by four different edemogenic agents, suggesting a potential role of selepressin in the clinical management of sepsis.
...
PMID:Protective Mechanism of the Selective Vasopressin V
1A
Receptor Agonist Selepressin against Endothelial Barrier Dysfunction. 3294 78
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