While diabetes is no longer a death sentence (thanks to the development of insulin therapies), diabetics are still subject to a large host of health problems as a result of their condition. One of these issues is the issue of diabetic nephropathy, damage that occurs to the kidneys.
This is your kidney:
(Via wikipedia)
Kidneys are some extremely important things. They are the big filtration system for your blood. Every time your blood goes through the kidneys, it is carefully filtered, as the first step in the formation of urine.
Now, this is your GLOMERULUS. Glomeruli are little tufts of blood vessels (capillaries, actually) that are the first step in filtering your blood in your kidney.
(Via Wikipedia)
Each of these little glomeruli are connected with a stalk to the main body. When people with diabetes suffer from nephropathy, the stalks connecting the glomeruli expand, scarring and cutting off the blood supply to the glomeruli, and creating problems with kidney function.
And now we come to the difference between men and women. When it comes to most kidney problems, women get PROTECTED. The hypothesis is that estrogens may be protective against problems in the kidney. But in diabetes, the odds are against us, with women getting kidney problems just as much as men, and it appears that estrogen receptors in the kidney may hurt rather than help.
And this is where we get into studies of Estrogen receptors…and their many, many splice variants.
Irsik et al. “Protein levels of Estrogen Receptor αlpha splice variants are
augmented in non-reproductive organs” Nebraska Medical Center, presented at Experimental Biology, 2011.
By now I’m sure most of you know that estrogen is found in women and men, and performs far more functions than those determining sex. Estrogen receptors are found all over the body, and may be able to modulate the functions of many organs. It has recently been found that estrogen receptors come in a variety of flavors, splice variants that are from the same DNA, but the proteins form up in slightly different ways. The original flavor of the estrogen receptor is the ERalpha66. That’s the full length receptor, but two other variants have recently been discovered, slightly shorter receptors called ERalpha46 and ERalpha36.
The discovery of these proteins was kind of a surprise. When scientists first knocked out the ERalpha66 receptor, they thought that they would completely knock out estrogen signaling. This turned out not to be true, and the splice variants were found. Of course the first areas of interest to look at were the sex organs, but now scientists are beginning to look at other organs. In particular, organs like the kidney.
When Irsik et al examined the kidney for splice variants of the estrogen receptor, they found that ERalpha36 was expressed up to 5 times higher than in reproductive organs. This is an interesting finding in itself (function of the ERalpha36 receptor could have a big impact on things like diabetic nephropathy), but what was even better was WHERE the receptor was being found.
Normal estrogen receptor signaling happens like this: estrogen from the blood goes on through the cell membrane, binding to an estrogen receptor that is inside the cell body. The estrogen receptor and the bound estrogen then head to the nucleus, where they change what DNA is expressed. But there are other ways to do estrogen signaling. And Irsik et al found that the ERalpha36 splice variant of the receptor is actually expressed in the cell MEMBRANE, where it interacts with another receptor called GPR30. What this means, we don’t know, but it certainly makes the ERalpha36 look like a good bit more than just a shorter version of the estrogen receptor.
So what does this all have to do with kidney function, you might ask? Well, if ERalpha36 is VERY highly expressed in the kidney, expression levels may determine how protected the kidney is from damage. Women are in general protected from kidney damage, and its thought that high levels of estrogen are the reason. These estrogen receptors might be the key.
And again: what does this have to do with diabetes? Diabetes isn’t just about insulin, it disrupts many functions in the body, including the production of testosterone and ESTROGEN. The changes in estrogen and the role of the ERalpha36 receptor in the kidney might explain to some extent why diabetics suffer from nephropathy, and could provide ideas as to how to treat the problems. In fact, Irsik’s next step is to look at the ERalpha36 splice variant in a mouse diabetes model, to see how expression differs, and what this could mean for kidney function.
PS: I got a chance to chat with Debra and Pascale about their research, and Debra, in the spirit of truly awesome geeks everywhere, got into the spirit to present at Experimental Biology by getting the KIDNEY and the American Physiological Society logo put into her PEDICURE!!! Which of course, she wore with some adorable shoes. She let me have a photo!
(Kidney’s on the left, APS logo is on the right. Awesome, right???)
