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25-D does not activate the Human VDR
 Moderated by: Prof Trevor Marshall Page:  First Page Previous Page  1  2   
 

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Prof Trevor Marshall
Foundation Staff


Joined: Fri Jul 9th, 2004
Location: Thousand Oaks, California USA
Posts: 14864
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 Posted: Sat Apr 21st, 2012 09:01

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You will never silence the naysayers :)

As for in-vitro evidence, we have some, but not strong enough for us to publish. Others might, but we will not... Haven't seen any in-vovo results.

Remember that the VDR is an awfully difficult thing to measure. It is so dependent on the environment around it, the entire metabolism. When isolated in-vitro, typically they use a very very high concentration so as to get the results they expect. One problem, for example, is the use of the solvent DMSO in processing the tissue in-vitro. What effect does that have on the immune system at high concentrations? (remember that you will find folk using it as a 'treatment' if you glance around the web). Yet everybody seems to use it... the whole research ecosystem often seems upside-down to me...

..Trevor..
 

Jigsaw
Research Team


Joined: Thu Jul 13th, 2006
Location: Australia
Posts: 935
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 Posted: Sat Apr 21st, 2012 16:08

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luxman wrote: : is there any in vitro or in vivo evidence published anywhere on the agonistic behaviour of Olmesartan on the VDR?
  I am happy for now with the data on the effects of ARBs on angiotensin II levels. All raise the levels (as expected) except olmesartan which lowers them.
  This is consistent with olmesartan agonism of the VDR which inhibits the production of angiotensinogen and renin. Renin catalyses the first step in the sequence:
angiotensinogen  -----> angiotensin I ------> angiotensin II



____________________
MP Feb,'07. Arthritis'78. CKD'07. Last 25D=7ng/ml Feb'13.
Prof Trevor Marshall
Foundation Staff


Joined: Fri Jul 9th, 2004
Location: Thousand Oaks, California USA
Posts: 14864
Status:  Offline
 Posted: Sat Apr 21st, 2012 18:13

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Indeed, Jigsaw, all of the clinical phenomena (we have seen to date) fit well with our model.

There are other receptors very similar to the VDR about which nothing is known yet (like CAR), and so there may be other mechanisms in play. But I have seen nothing yet to dilute my confidence that a direct agonist action on VDR is most likely. Which is what my molecular dynamics emulations confirm.

Also note this paper, with 1,25-D raising creatinine, just like olmesartan does:

http://www.ncbi.nlm.nih.gov/pubmed/21716260

..Trevor..
 


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