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17
Abstracts
THE ROLE OF UBIQUITYLATION IN THE CONTROL OF NA+ HOMEOSTASIS AND BLOOD PRESSURE CONTROL
Staub, O.
Department of Pharmacology & Toxicology, University of Lausanne, Lausanne, Switzerland
The kidneys play a major role in Na+ homeostasis and consequently in blood volume and pressure regulation. This is highlighted by the genetic linkage of numerous genetic diseases causing either salt-sensitive hypo- or hypertension to mutations affecting the regulation of ion transporters or channels in the kidney (e.g. Liddle's, Familial Hyperkalemic Hypertension (FHHt), or Gitelman's syndrome). It is also well established that ubiquitylation (i.e. the post-translational modification of proteins with ubiquitin-polypeptides) is crucially involved in these processes. As an example, the intrinsic activity and cell surface expression of the epithelial Na+ channel ENaC is negatively regulated by the ubiquitin-protein ligase NEDD4-2. In Liddle's syndrome, characterized by hypertension, hypokalemic metabolic alkalosis and elevated ENaC activity, the regulation by NEDD4-2 is impaired by mutations on ENaC that inactivate the interaction site with
ENaC. Recently, we have shown both in vitro and in vivo that NEDD4-2 is also involved in the control of the thia-zide-sensitive Na+,Q-cotransporter NCC. Indeed, NEDD4-2 co-immunoprecipitates with NCC induces its ubiquitylation and downregulates NCC at the cell surface in vitro. Moreover, in inducible, nephron-specific NEDD4-2 KO mice NCC is strongly upregulated. It has been shown that NEDD4-2 is regulated by kinases such as the aldosterone-induced SGK1 kinase, or the WNK kinas-es. Certain kindred of FHHt, characterized by hypertension, hyperkalemia and metabolic acidosis and increased NCC activity, are linked to mutations in KLHL3 or CULLIN3, two subunits of ubiquitin-protein ligase complex, further highlighting the importance of the ubiquitin system in salt regulation and blood pressure control. We will discuss recent progress in the understanding of the role of ubiquitin in this field.
CELL SWELLING-INDUCED HORMONE SECRETION - PATHOPHYSIOLOGICAL IMPLICATIONS
Strbak, V.1' , Bacova, Z.1' , and Ravingerova, T.3
1 Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia
2 Department of Pathophysiology, Medical Faculty, Slovak Medical University, Bratislava, Slovakia
3 Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovakia
Cell swelling induces exocytosis of protein and peptide hormones after exposure of cells to relative hyposmolarity or permeant agents. Phenomenon utilizes unique signaling pathway; resistance to endogenous inhibitors is its frequent attribute, secretion involves also secretory vesicles not involved in conventional stimulation due to participation of sequential exocytosis as dominating mechanism. Hyposmosis-induced secretion is more sensitive to high cellular cholesterol than conventional one. These features determine also different behavior of hormone secretion at some pathological situations. Cell swelling-induced exocy-tosis possesses limited selectivity, cells specifically involved in water and salt regulation retain their specific response to osmotic stimuli; e.g. neurons of the hypothalamic supraoptic and paraventricular nuclei release oxytocin, vasopressin and angiotensin II and III in response to hyperosmotic stimulation. This specific response could be obviated by GdCl3 and
at these conditions general unspecific response (exocytosis) to hyposmotic stimuli emerges. This phenomenon could play a role in the syndrome of inappropriate secretion of antidiuretic hormone - SIADH when specific reception of osmolality is disturbed. Clinical experience indicates that unexpected, frequent, and prolonged hypoglycemia is a substantial problem after alcohol ingestion in diabetic subjects. Ethanol in clinically relevant concentration in isosmotic medium induced dose-dependent release of insulin in vitro. Ethanol as permeant enters also neurons and pituitary cells and induces swelling and release of peptides from neurons and pituitary. It is likely that release of beta-endorphin from pituitary cells induced by hypotonicity could be induced also by ethanol. Swelling-induced products could be mediators of ischemic preconditioning involved also in protection of diabetic heart. Supported by VEGA SR 2/0132/12 and 2/0054/11, APVV 486-10 and Chicago Diabetes Project.
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Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24-68
