One of the hallmarks of autosomal dominant polycystic kidney disease (ADPKD) is hypertension. True, most patients with advanced kidney disease get hypertension anyways--but often the degree of hypertension in ADPKD patients seems to be especially high. Is there something about the function of the polycystin proteins which explains the high blood pressure?A recent article by Sharif-Naeini et al in this month's issue of Cell claims a pressure-sensing role for the polycystins. ADPKD is caused by mutations in two genes, PKD1 and PKD2, which encode for membrane proteins termed TRPP1 and TRPP2, respectively. It appears these genes function via regulating local calcium fluxes in and out of the cell. Although most efforts to understand TRPP1 and TRPP2 function have focused on renal tubular epithelial cells (since that's where cysts come from), a variety of extra-renal phenotypes are also observed. In this paper, the authors generated mice deficient in TRPP1 or TRPP2 ONLY in smooth muscle cells. Importantly, they found that the balance of TRPP1 and TRPP2 levels was critical for the ability of arterial smooth muscle to maintain appropriate blood pressure. These results imply that function of the polycystins may be different depending on cell type, and suggest a possible mechanism by which ADPKD patients may be especially prone to the development of abnormalities in blood pressure regulation.
Deletion of trpp1 and trpp2 using this particular transgenic smooth muscle promoter (Tg Sm22) cre mouse line actually had no affect on blood pressure (although the methods used for determining blood pressure were subpar- tale cuff and anesthetized via femoral artery). Each of the experiments were carried our on isolated vessels (mesenteric or aortic) which likely do not represent true resistance vessels. These vessels did have abnormalities that would suggest a greater in vivo role for trpp1 and trpp2, this system does not answer the question as to how these regulate blood pressure in vivo, but rather ex vivo. I do feel that this is a rather intriguing article and would like to see what kind of abnormalities would have been seen using a more robust smooth muscle cre line (such as the newly developed knock-in sm22 cre or SMMHC cre). Overall, it is great to see to of my interests come together, PKD and vascular biology. I wonder if trpp1 and trpp2 have any role regulating renin release in the JG cell?
ReplyDeleteMatt Sparks
Great comments, Matt. Yes, I did pick up on the fact that the mice did not actually have BP changes in vivo...to be honest, I'm not sure how difficult or easy it is to make mice hypertensive.
ReplyDeleteOne of my interests in this article is that it suggests that the polycystins trpp1 and trpp2 may act in a cilia-independent fashion. There has been a lot of attention on cilia as "flow sensors" in the kidney. This still may be true (I'm not 100% convinced it is), but based on this paper it looks like these proteins can also detect smooth muscle stretch.
Nice seeing you at ASN. Just found out I'm supposed to be in someone's wedding that's the same time as next year's ASN in Denver, so looks like no skiing in the Rockies for me :(
Nathan, "making" mice hypertensive is what our lab does every day. Can be done by a variety of means (high salt diet, ang II pump, LNAME, etc.) It's does take some surgical skill to implant devices in the carotid artery of mice for monitoring BP in vivo. I would like to see how deleting trpp1 and trpp2 in smooth muscle would affect BP in a better model. I have used this exact cre line they used in this article and it has several problems which I documented in my earlier post (namely, it does not delete resistance vessels). I doubt they would see a BP phenotype in this system.
ReplyDeleteSorry you will miss ASN next year. Hope all is well and have a good thanksgiving.
Matt Sparks