Solving Kidney Mysteries #ExpBio

Mar 29 2015 Published by under EB 2015

UPJ

Gross Urinary Anatomy

 

As a pediatric nephrologist (children's kidney doctor), hydronephrosis or water on the kidney is one of the most common problems I see. The kidney can be thought of as two general parts: (1) A bunch of blood vessels that filter “dirty” blood and return it to the body after cleansing and (2) Tubes made of cells that carry filtered material from the blood vessels, taking good stuff back into the body and taking out more bad stuff to make urine.

As these tubules travel through the kidney, they eventually come together to form bigger and bigger tubes until they form the pelvis (see diagram), the main part of the urine collecting system within the kidney. When these central collecting systems look enlarged on ultrasound or other study, we call it hydronephrosis.

The pelvis of the kidney becomes a fine muscular tube, the ureter, once it leaves the kidney. This transitional area, the ureteropelvic junction (UPJ, lower image) is a fairly common place for obstruction to develop before children are born. In most cases, the actual obstruction resolves early on, leaving an enlarged but fully functional collecting system. Think of a balloon that you have blown up and then the air let out. It is never as tight as it was before (and so seems a little floppy), but nothing is blocking it up.

In some cases, the UPJ obstruction persists after birth but gets better over months to years. In other cases, the obstruction tightens and may require surgical repair or result in the loss of kidney function.

We know all of this from following lots and lots of kids with UPJ obstruction for years. What we do not know is why this portion of the collecting system is so prone to obstruction.

A Novel Transgenic Mouse Model for Congenital Obstructive Nephropathy; AJ Lee et al

One reason we know so little about the how and why of UPJ obstruction is that there have been no non-surgical models where it develops spontaneously. That no longer seems to be a problem as this group, led by Ben Fogelgren at the University of Hawaii (I'm available to collaborate and I will come to you) now has a mouse that develops severe UPJ obstruction. Unfortunately, these mice have complete anuria, resulting in death at birth.

How did they do this? The model involves a conditional knock-out of Sec10 in the ureteric buds of embryonic mice. These cells are destined to become the ureter and pelvis within the kidney. Sec10 is a protein in exocysts, structures in the cells that help other proteins get to their correct location.

Cells run on proteins. Some have to be in the apical (top) membrane, some have to be in the basal (bottom) membrane, while others have to attach to stuff within the cell. The cells in the developing ureter have a number of proteins that must be on the apical membrane that lines the tube. One of these proteins, Uroplakin 3, fails to end up there in these mice. The cells look abnormal, and other cells (muscle or scar cells) grow more until the ureter tube closes.

This model obviously has some differences from what we see in people. Most children have mild UPJ obstruction only on one side, so it seems likely that environmental factors may disrupt these processes transiently in clinical situations. However, this model should increase our understanding of what controls this process and why it happens in this particular location.

This model provides an important opportunity to study a major cause of pediatric kidney problems. I look forward to seeing a lot more data from this lab!

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