IN BRIEF

Uroplakin Plaque Key to Protecting Kidney During Urinary Tract Obstruction

May 24, 2019
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Plaque appears to help remodel urothelium, allowing kidney to hold excess urine without damage

Urinary tract obstruction (UTO) is the leading cause of chronic kidney disease and end-stage renal disease in children. But the extent of damage caused by obstruction differs from child to child.

Researchers at Nationwide Children’s Hospital studying why suggest that uroplakin plaque deposition is essential to kidney urothelium remodeling that enables the organ to hold large amounts of urine while maintaining renal structural stability.

The researchers observed evidence of the process, which they informally call the “bladderization” of the kidney, in mouse models of congenital and acquired UTO.

“As hydronephrosis worsened in the models, there was no renal functional decline despite having massive kidneys with huge volumes of urine and even parenchymal thinning,” says Ashley Jackson, PhD, a postdoctoral fellow in the Center for Clinical and Translational Research at The Research Institute at Nationwide Children’s and study leader. “These are findings you would see when using ultrasound to profile children who maintained function.”

The investigators believe that parts of the process may eventually prove useful for diagnosing and treating UTO. Their study is published in the American Journal of Physiology-Renal Physiology.

“UTO diagnosis can be difficult if only one kidney is involved and intervention can be controversial,” says Brian Becknell, MD, PhD, a pediatric nephrologist, principal investigator in the Center for Clinical and Translational Research and senior author of the study. “There is some evidence that patients with partial obstruction of one kidney can have resolution without surgery.”

But what’s happening in the kidney during resolution, and why an obstruction will resolve in one child and not another, is largely unknown.

In models of congenital UTO that showed no functional decline, “we did a microarray study looking at the transcripts most significantly up and down,” Dr. Jackson says. “We found a urothelial gene signature, which was quite odd. The urothelium makes up such a miniscule proportion of the kidney yet it stood out as a key signature in response to obstruction. All the major uroplakins were significantly elevated as well.”

Uroplakins are protein building blocks of uroplakin plaque.

Imaging showed urothelium remodeling. Uroplakin plaques formed a continuous plaque that stretched and deformed but appeared not to transduce high pressure to the parenchyma, says Dr. Becknell, who is also an assistant professor of pediatrics at The Ohio State University College of Medicine.

Further testing showed the importance of uroplakins, Dr. Jackson says. “When we depleted them, it led to worse outcomes, including accelerated parenchymal loss, renal failure and, in some cases, failure to thrive.”

All together, the findings have led the investigators to speculate that some children who require intervention for a UTO may benefit from therapies designed to promote uroplakin plaque formation.

Drs. Jackson and Becknell are now working to define the precise roles of the uroplakin plaque during UTO and investigating the function of uroplakin-expressing renal urothelial cells, which they hypothesize act as sensors that trigger uroplakin signaling and urothelium remodeling.

The researchers are studying whether urothelial protein in the urine could indicate which children are most or least at risk from UTO damage. They are also laying the groundwork toward developing therapies, especially noninvasive therapies for congenital UTO diagnosed in utero, which can be fatal.

Citation: Jackson AR, Li B, Cohen SH, Ching CB, McHugh KM, Becknell B. The uroplakin plaque promotes renal structural integrity during congenital and urinary tract obstruction. American Journal of Physiology-Renal Physiology. 2018 Oct 1;315(4):F1019-F1031.