Renal Chloride Chanels and Blood Pressure Regulati.. (CLOPRESS)
Renal Chloride Chanels and Blood Pressure Regulation
Date du début: 1 mai 2015,
Date de fin: 30 avr. 2017
Hypertension, or elevated arterial blood pressure, is a significant global health concern. A major cause of hypertension is the abnormality in salt (NaCl) handling in distal nephron segments within kidney. Although there has been long a debate with regard to the relative importance of Na+ vs. Cl- in inducing salt-sensitive hypertension, previous research demonstrated that excess intake of Cl- could lead to severe salt-sensitive hypertension. Thus, better understanding on molecular mechanisms of renal Cl- handling would provide useful insights in treatment of hypertension. Previous studies largely focused on the identification and regulation of apically expressed Cl- transporters, including Na+-Cl- cotransporter, Na+-K+-2Cl- cotransporter (NKCC1/NKCC2) and pendrin, but mechanisms and regulation of Cl- transporters on basolateral membranes (i.e. an exit of Cl- into the interstitial space) remains poorly described. Thus, the current proposal will investigate the physiological role of basolateral Cl- channel distributed in distal nephron, specifically ClC-kb. Using a transgenic ClC-kb knockout line of mice, I propose to investigate the physiological role of this channel within isolated tubule and at the whole animal level. In addition, ClC-kb channel is known to interact with a functional β-subunit, barttin, and this interaction could affect Cl- conductance. I propose to investigate the molecular mechanisms by which barttin can affect ClC-kb-mediated chloride transport. The proposed studies will shed new insights into the molecular mechanisms of Cl- reabsorption in distal nephron, and could provide a basis for novel approach in treatment of hypertension.
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