S-27-7: ROLE OF THE UBIQUITIN LIGASE KLHL3 IN BLOOD PRESSURE AND ELECTROLYTE HOMEOSTASIS

Abstract

Genetic studies on familial hypertensive and hypotensive disorders followed by the biochemical analysis have provided fundamental insights into the regulation of NaCl transport mechanisms in the renal nephron. One such example is the analysis of pseudohypoaldosteronism type II (also known as Gordon syndrome), which led to the identification of previously unrecognized constituents engaged in electrolyte and blood pressure homeostasis. Kelch-like 3 (KLHL3) is a component of cullin-RING (really interesting new gene) ubiquitin ligase whose mutations have been shown to cause pseudohypoaldosteronism type II through several mechanisms, including impaired ability to bind target substrates and altered protein stability. Studies to date have also provided insights into the physiological mechanisms that regulate KLHL3 function, which involves phosphorylation at the substrate-binding domain that is counter-regulated by protein kinase C and phosphatase calcineurin. Moreover, accumulating data indicate that these mechanisms are likely involved in the acquired forms of hypertension, particularly those associated with lifestyle related disorders such as obesity. Recent advance on the function of KLHL3 in the kidney, as well as its pathogenic roles in electrolyte disorders, will be reviewed and discussed.