Bradykinin Signaling Counteracts cAMP-elicited aquaporin 2 translocation in renal cells
| Title: | Bradykinin Signaling Counteracts cAMP-elicited aquaporin 2 translocation in renal cells |
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| Authors: | Tamma, Grazia; Carmosino, Monica; Svelto, Maria; Valenti, Giovanna |
| Publisher: | Journal of American Society of Nephrology |
| Date Published: | October 01, 2005 |
| Reference Number: | 697 |
Bradykinin (BK) is one of the most important peptides regulating vascular tone, water, and ionic balance in the body, playing a key role in controlling BP. It is interesting that patients with essential hypertension excrete less BK than normotensive individuals. For elucidating the mechanism by which BK regulates renal water transport that contributes to its antihypertensive effect, aquaporin 2 (AQP2)-transfected collecting duct CD8 cells, expressing the BK type II receptor (BK2R), were used as an experimental model. In CD8 cells, BK pretreatment impaired forskolin-induced AQP2 translocation to the apical plasma membrane. For clarifying the signal transduction cascade associated with this effect, whether BK induced an increase in cytosolic calcium, via the G protein Gq, known to be coupled to BK2R, first was investigated. Spectrofluorometry using fura-2-AM revealed that 100 nM BK elicited a significant increase in Ca(i), which was abolished by the receptor antagonist HOE-140. BK acts through BK2R coupled to both Gq and Galpha13, a known upstream effector of Rho protein. In CD8 cells, BK causes an increase in Rho activity, likely as a result of Galpha13 activation. This results in stabilization of the cortical F-actin network, thus impairing AQP2 trafficking. These effects counteract physiologic vasopressin stimulation, which instead has an opposite effect on actin network organization through Rho inactivation.
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This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)
Tamma, et al., used laboratory cell cultures of rabbit kidney cells to study the chemical sequence involved in BK activation, and the effect this sequence had on the movement of the aquaporin-2 (AQP2) protein. Normally, the AVP/V2R sequence results in the AQP2 protein moving from the cell interior to the top (apical) section of the cell membrane. There, AQP2 acts as a channel through which water can enter the cell. This is how the kidney reabsorbs water in its collecting duct, and the result is concentrated urine. The sequence is as follows: AP binds with V2R. This induces an increase of intracellular cAMP levels by means of the stimulatory Gs protein and adenylate cyclase. This activates protein kinase A, which adds a phosphate group (through a process known as phosphorylation) to AQP2. This stimulates AQP2 to move from the cell interior to the cell membrane, aided in part by a partial breakdown of the F-actin network (specifically, the actin filament) brought about by the inhibition of proteins of the Rho family that occur in this sequence.
The research team’s data showed that BK increases the intracellular calcium levels of the rabbit kidney cells, but that this was not responsible for the inhibitory effect it has on AQP2’s movement to the apical cell. In their previous research, the team had observed that that the activation of the Rho protein impairs AQP2 movement to the kidney cell membrane. In this study, they observed that BK increased the Ga13 protein (which Rho can bind to). This indicated that BK might activate Ga13, which in turn may stimulate Rho protein activity. This is important because Rho activation results in a stabilization of the F-actin network. For AQP2 to be able to move to the cell membrane, the F-actin network must be destabilized.
Thus, Tamma, et al, concluded that the BK/BK2R signaling sequence counteracts the movement of AQP2 to the apical membrane that is signaled by the AVP/V2R sequence. It does this linking with BK2R which is coupled to both the Gq and the Ga13 proteins. This causes an increase in Rho activity, which stabilizes the F-actin network.