Thursday, November 6, 2008

Proliferation Requirement for Cystogenesis

I'm suffering from information overload after my first day at the 2008 ASN in Philadelphia, PA. I attended a series of great talks and have a whole list of possible blog topics in my notebook. For now, I'll briefly discuss one of the central themes of the polycystic kidney disease session; namely, that cyst development occurs in the context of cell proliferation.

To back up a bit: PKD1 and PKD 2 are the two main disease genes for autosomal dominant polycystic kidney disease. Complete knockout of PKD1 and PKD2 in mice results in massive cystic dilatation at birth. However, we know that human patients with this disease do not usually develop large cyst growth and advanced CKD often into their 5th decades. In order to better duplicate this physiology, researchers have developed "conditional knockout" mice in which the expression of Pkd1 can be switched OFF at various ages of mouse life by injecting it with tamoxifen. It turns out that turning off PKD1 after several months of life leads to much more delayed cyst growth, leading investigators to hypothesize that the reason cyst growth occurs so vigorously in younger kidneys is because the nephrons are still actively proliferating and are therefore "primed" to form cysts. Interestingly, subjecting conditional knockout mouse kidney to hypoxia/ischemia leads once again to more rapid cystogenesis, providing further evidence for the idea that cystogenesis is favored in an environment of rapid proliferation.

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