Urinary tract obstruction is a collection of abnormalities that includes posterior urethral valves, vesicoureteral reflux, and hydronephrosis – common birth defects accounting for 20 percent of chronic kidney failure in children. Understanding the genetic origins and complications of urinary tract abnormalities is among the research investigations of Cathy Lee Mendelsohn, PhD, a developmental biologist in the Division of Genetics and Development and Pathology in the Department of Urology at NewYork-Presbyterian/Columbia University Irving Medical Center.

Dr. Cathy Lee Mendelsohn

“Historically, developmental biologists have worked in mouse models looking at congenital abnormalities, which is how I came to focus on congenital abnormalities of the kidney and urinary tract, referred to as CAKUT,” says Dr. Mendelsohn. “These abnormalities affect a number of different organs at the same time – the kidney, ureter, bladder, and urethra. There are also a number of defects that all fit under this one umbrella.”

Several years ago, Dr. Mendelsohn’s lab used mouse models to establish the sequence of events that occurs during ureter maturation, a process where primitive ureters make direct connections with the bladder, which when defective, is a common cause of urinary tract dysfunction. “Mutants with abnormal retinoic acid signaling develop massive bilateral hydronephrosis,” says Dr. Mendelsohn. “Our studies suggest that these abnormalities are linked to defective apoptosis during ureter maturation, which normally depends on CASP9. Our findings further suggest that CASP9 may be a direct transcriptional target of retinoids.”

Dr. Jonathan M. Barasch

Dr. Ali Gharavi

In her current research, Dr. Mendelsohn joins Columbia nephrologists Jonathan M. Barasch, MD, PhD, and Ali Gharavi, MD, in Columbia University’s George O’Brien Urological Center, which brings together research programs in human genetics and mouse models to address the causes of congenital urinary tract malformations. Their collective investigations in this NIH-funded project are centered on identifying genetic mutations in mice that, in humans, are linked to causes of congenital urinary tract malformations. “The scientific aims of our research projects are highly interconnected, focused on identifying the genetic and embryological causes of obstruction and the related events that lead to renal disease,” says Dr. Mendelsohn. “The administrative core of the center aims to promote a vigorous exchange of ideas and data sharing between projects and with other researchers in the field of benign urology.”

“We are like detectives going back in time and looking at genetic models to try and find out what was the first thing that went wrong in development,” continues Dr. Mendelsohn, who notes that there is currently a shift from classic anatomic theories to contemporary biological views of CAKUT. “When you get back to the beginning, it starts to make more sense because some very basic events take place. The ureteric bud theory, from Mackie and Stevens, says that if a particular event happens too late, too early, too fast, or too slow, everything else downstream from that is going to be affected. You can have a structure that is common and involves different organs that are abnormal, or it can be a gene that is used in five or six different organs simultaneously. In the old days, the thinking was all about the physical characteristics of what went wrong. But now we know that all of the very important genetic pathways are used over and over and over again.”

A defective gene can affect multiple tissues, multiple organs, and multiple cell types, says Dr. Mendelsohn. “There are two possibilities from which one can get these syndromes – from a common event that went awry or from a gene like RET or other genes that are important in the kidney, ureter, and Wolffian duct. Abnormalities can develop in all of those tissues if you have mutations.”

“By identifying the gene mutations, we may make it possible for physicians to determine who is going to need surgery and who is not and what is likely to be a problem or not for a patient in the future.”

— Dr. Cathy Lee Mendelsohn

Dr. Mendelsohn’s current investigation seeks to determine if the cell types and genes in mice are the same as in humans in order to be able to integrate what they are learning. “Dr. Barasch and Dr. Gharavi are also geneticists who are looking for mutations in the families they are treating,” she says. “For example, a mother, a father, and a child might all have a mutation and the child has CAKUT,” she says. “It’s usually a region with four or five genes that are mutated in all of those individuals, or in individuals that cross a group. Then the question in the group with CAKUT becomes: Is that mutation the cause of the CAKUT?”

Once a mutation and a gene are identified, Dr. Mendelsohn and her lab team study what occurs when they knock out the gene in a mouse model. Or they create the same mutation in the mouse and if a defect develops, they can be certain it is the mutated gene that caused the congenital abnormality. “We take a cross section of the animal’s tissue and look at it after the disease manifests itself,” she says. “Then we go back in time to identify which events were abnormal – either by histology or by looking at gene expression changes. That’s how we find out the primary cause of the defect.”

“And why do we even want to know?” asks Dr. Mendelsohn. “The reason is because some of these conditions will self-resolve, and a doctor would not intervene. However, in other cases, as with posterior urethral valves – an obstruction of the urethra that is part of this syndrome – a high rate of children will go on to dialysis. These findings enable a physician to triage patients and figure out what is likely and not likely to happen.”

“One day I believe we will be able to actually correct the mutations,” adds Dr. Mendelsohn. “But for now, at least by identifying the gene mutations, we may make it possible for physicians to determine who is going to need surgery and who is not and what is likely to be a problem or not for a patient in the future.”