Modulation of renal NaCl transporter via angiotensin II-WNK4-SPAK signaling pathway. (360G-Wellcome-091415_Z_10_Z)
The thiazide-sensitive Na+:Cl- cotransporter (NCC) is the main pathway for salt reabsorption in the distal convoluted tubule in mammalian kidney. Work recently done by others have shown that angiotensin II, the pro-hypertensive hormone, increases the trafficking of NCC to the apical membrane, and thus activity, and we have recently proposed a molecular mechanism for such regulation. We have demonstrated in Xenopus oocytes that upon angiotensin II signal, WNK4 turns from an inhibitor to an activa tor of NCC and that this effect depends on WNK4 activating effect on another serine/threonine kinase known as SPAK. Thus, WNK4 behaves as a molecular switcher that changes the kidney from a salt-losing to a salt retaining state. This is a very important molecular mechanism increasing our understanding of blood pressures regulation. However, because our observations were done using an in vitro model, the proposed mechanism required to be confirmed, analyzed, and characterized in vivo. In this s tudy we plan to use three different genetically altered mice in which the expression of WNK4 or SPAK has been altered to analyze the effect of a physiological condition (low salt diet, a high angiotensin state) and of a pathophysiological condition (arterial hypertension induced by angiotensin II administration).
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Grant Details
Amount Awarded | 230172 |
Applicant Surname | Alessi |
Approval Committee | Physiological Sciences Funding Committee |
Award Date | 2010-04-29T00:00:00+00:00 |
Financial Year | 2009/10 |
Grant Programme: Title | Project funding: Inactive scheme |
Internal ID | 091415/Z/10/Z |
Lead Applicant | Prof Dario Alessi |
Other Applicant(s) | Prof Gerardo Gamba |
Partnership Value | 230172 |
Planned Dates: End Date | 2013-12-31T00:00:00+00:00 |
Planned Dates: Start Date | 2010-07-01T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | Scotland |