Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecule found to be critical for kidney development

09.09.2003


By taking advantage of techniques developed in the search for Alzheimer’s treatments, a team of researchers has discovered that a molecule called Notch is essential for the development of critical kidney cells. The study, published online and in the Oct. 15 issue of the journal Development, provides key information about kidney development that could have implications for tissue regeneration.



"Tissue transplantation is fantastic but it would be so much better if we could instead raise organs from a patient’s own cells," says lead investigator Raphael Kopan, Ph.D., associate professor of medicine and of molecular biology and pharmacology at Washington University School of Medicine in St. Louis. "Before we can actually trick cells into doing what we want them to do we really need to understand every detail about how the organ is put together."

Using an antibody that specifically identifies the active form of Notch, Kopan’s group observed that the protein is extremely active in the kidney at an earlier stage than previously thought. So they teamed up with kidney development expert Jeffrey H. Miner, Ph.D., associate professor of medicine and of cell biology and physiology, to investigate further. First, though, they had to resolve a methodological conundrum: How do you study the effect of Notch in the kidney if animals without Notch die before the kidney begins to form?


The answer came from an entirely different field: Alzheimer’s disease. In 2001, Kopan’s team discovered that a group of potential Alzheimer’s drugs that inhibit a protein complex called gamma-secretase also interfere with Notch. For clinical purposes, the drugs have since been refined to minimize their potentially dangerous effects on Notch. But drugs that severely inhibit this protein are perfect for studying its activity in laboratory animals.

"We took advantage of developments in different fields to allow us to do this analysis," says Kopan. "Without collaborating and combining our knowledge, we would not have been able to conduct this study."

The team removed both kidneys from normal mice during early development and placed them in organ culture. They treated one kidney from each mouse with a gamma-secretase inhibitor and showed that this process prevented all Notch signaling. The second kidney from each animal was used for comparison.

After three days of treatment with the inhibitor there were fewer and less developed tubular structures in the treated compared to the untreated kidneys. These differences became more pronounced after five days of treatment: Tubes in untreated tissue branched an average of 10 times and the tips of these branches had consistent, small diameters; tubes in treated tissue only branched a maximum of eight times and their branches were more irregularly shaped.

For the most part, the treated cells successfully passed through the first stage of development, in which they evolved from embryonic, precursor cells into epithelial cells, which form the lining of the organ. But the most pronounced abnormalities occurred in the next stage of development, in which the cells become more specialized.

Urine is formed in the kidney’s functional units, called nephrons. Within each nephron are several structures, including a long, winding tube called the proximal tubule and octopus-shaped cells called podocytes that wrap their "feet" around blood vessels. After two days of treatment with the gamma-secretase inhibitor, neither podocytes nor proximal tubule cells formed. Another nephron structure, the distal tubule, was not disturbed.

"The most exciting finding was that Notch signaling appears to tell some cells to become podocytes from a mass of non-specialized epithelial cells," Miner says. "This shows that Notch is involved at an earlier stage of podocyte development than any other factor that’s been identified so far."

Even more surprising was that the tissue lost the ability to form podocytes after a certain amount of time. If Notch signaling resumed after two days, podocytes recovered. But if it did not resume until three days or more, the cells instead developed into those that comprise the proximal tubule.

"It’s as if the cell can tell time," Kopan explains. "After three or four days without Notch signaling, it realizes it will never become a podocyte and decides to respond to the next signal it receives."

Next, the team hopes to further differentiate the role of Notch in formation of each component of the nephron, and to determine the specific genes responsible for this particular developmental pathway.


Cheng HT, Miner JH, Lin MH, Tansey MG, Roth K, Kopan R. g-Secretase activity is dispensable for mesenchyme-to-epithelium transition but required for podoctye and proximal tubule formation in developing mouse kidney. Development, vol. 130, pp. 5031-5042, Oct. 15, 2003.

Funding from the National Institutes of Health, the Alzheimer’s Association, the Zenith award, the American Heart Association and the March of Dimes supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Gila Z. Reckess | EurekAlert!
Further information:
http://medinfo.wustl.edu/

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Epoxy compound gets a graphene bump

14.11.2018 | Materials Sciences

Microgel powder fights infection and helps wounds heal

14.11.2018 | Health and Medicine

How algae and carbon fibers could sustainably reduce the athmospheric carbon dioxide concentration

14.11.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>