Stem Cells And ABC Transporters Essential In Kidney Regeneration

In a study funded by the Dutch Kidney Foundation (DKF) a research group at Radboud University Nijmegen Medical Centre in the Netherlands, found that stem cells and ABC transporter proteins are indispensable for tubular regeneration after acute kidney injury.Said project leader Dr. Rosalinde Masereeuw: 'To our surprise, our knockout mice for the ABC transporters P-gp and BCRP, P-gycoprotein and breast cancer resistance protein, were protected against acute kidney damage. This was the opposite of what we expected since the transporters usually have a protective function in excreting potentially toxic compounds, while these mice lack expression. Moreover, when we cross transplanted bone marrow between normal mice and the knockouts it turned out that bone marrow from the knockouts was the source of protection.'

Regeneration

Acute kidney injury is an important cause for the need of acute hemodialysis and a source of kidney failure. On the other hand, the kidney has a remarkable capacity for recovery. Stem cells seemed to have a limited share in the repair process, but now this study suggests otherwise.

'It was known that stem cells from the bone marrow express P-gp and BCRP abundantly but will downregulate them at differentiation. Repair of tubular damage in the kidney depends primarily on local cells but stem cells are involved as well. Further, we observed an upregulation in the expression of the transporters during ischemic injury. .So we thought they might be important in renal regeneration.'

Transporter Proteins

ABC transporters (ATP binding cassette transporters) form a superfamily of highly conserved transporter proteins whose functions are not yet well understood. However, BCRP and especially P-gp have been studied in more detail in man. These cell membrane pumps are responsible for the transport of many substances, for instance drug molecules in the intestine. P-gp plays an important role in drug resistance of tumour cells.

Masereeuw: 'Our new hypothesis claims a bigger role for bone marrow derived stem cells in kidney regeneration. A possible mechanism is the infiltration of macrophages. These large immune cells have subgroups one of which increases damage but another supports tissue regeneration.'

Also, the study showed that mice without P-gp expression lose renal tubular function in a way comparable to Fanconi syndrome in man. BCRP knockouts, on the other hand, have a normal kidney function.

Blocking P-gp and BCRP

There is a great need for novel therapies that limit kidney damage after acute injury by toxic substances or shortage of oxygen, as in transplant kidneys which have no blood supply during transport. The results from this DKF study are pointing at inhibition of the transporters in kidney or bone marrow to strengthen the regenerative power of stem cells.

'Next, we will try to discover the mechanism by which stem cells and ABC transporters contribute to kidney repair', concludes Dr. Masereeuw, 'and we will test the effect of transporter blockers in our mouse models. We are convinced there are good opportunities here for new drug targets.'

Pollution-related Asthma May Start In The Womb

Children born in areas with increased traffic-related pollution may be at greater risk of developing asthma due to genetic changes acquired in the womb, according to new research from the University of Cincinnati (UC) and Columbia University Mailman School of Public Health.
In a study of umbilical cord blood from New York City children, researchers have discovered evidence of a possible new biomarker—an epigenetic alteration in the gene ACSL3—associated with prenatal exposure to polycyclic aromatic hydrocarbons (PAHs). These chemical compounds are created as byproducts of incomplete combustion from carbon-containing fuels, resulting in high levels in heavy-traffic areas. Exposure to PAHs has been linked to diseases such as cancer and childhood asthma.

Researchers say this finding provides a potential clue for predicting environmentally related asthma in children—particularly those born to mothers who live in high-traffic areas like Northern Manhattan and South Bronx when pregnant.

This is the first study to examine the effects of prenatal ambient air pollutant exposure on epigenetic changes linked to asthma. Epigenetic changes may disrupt the normal functioning of genes by affecting their expression but do not cause structural changes or mutations in the genes.

The team reports its findings in the Feb. 16, 2009, issue of PLoS One.

For this study, UC researchers teamed with Columbia's Mailman School of Public Health to study the relationship between prenatal PAH exposure and childhood asthma, hypothesizing that transplacental exposure to PAHs could "reprogram" fetal genes and lead to airway inflammation or asthma during childhood. Epigenetic reprogramming is the result of an organism's genes interacting with the environment.

"Our data support the concept that environmental exposures can interact with genes during key developmental periods to trigger disease onset later in life, and that tissues are being reprogrammed to become abnormal later," says Shuk-mei Ho, PhD, senior author of the paper, chair of UC's Department of Environmental Health and the director of the Center for Environmental Genetics.

"This research is aimed at detecting early signs of asthma risk so that we can better prevent this chronic disease that affects as many as 25 percent of children in Northern Manhattan and elsewhere," adds Frederica Perera, DrPH, professor of environmental health sciences and director of the Columbia Center for Children's Environmental Health (CCCEH) at the Mailman School of Public Health and co- first author on the paper.

Using biological specimens from the CCCEH birth cohort of mothers and children living in Northern Manhattan and the South Bronx, UC scientists analyzed umbilical cord white blood cell samples from 56 children for epigenetic alterations related to prenatal PAH exposure. (The mothers' exposure to PAHs was monitored during pregnancy using backpack air monitors).

The researchers found a significant association between changes in ACSL3 methylation—a gene expressed in the lung—and maternal PAH exposure. ACSL3 also was associated with a parental report of asthma symptoms in the children prior to age 5.

With confirmation in further studies, researchers say changes in the ACSL3 gene could serve as a novel biomarker for early diagnosis of pollution-related asthma.

"This study provides a blueprint for the discovery of epigenetic biomarkers relevant to other investigations of exposure-disease relationships in birth cohorts," says Wan-yee Tang, PhD, a UC research scientist and a co-first author on the paper.

"Understanding early predictors of asthma is an important area of investigation," adds Rachel Miller, MD, director of the CCCEH asthma project and study co-author, "because they represent potential clinical targets for intervention."

The CCCEH birth cohort was launched in 1998 to study the effects of prenatal exposure to common urban pollutants on the health of mothers and their children. Children in the cohort were born to non-smoking Dominican and African-American women in Northern Manhattan or the South Bronx and follow-up is ongoing.

Funding for the multi-institutional study comes from the National Institute of Environmental Health Sciences (NIEHS), the U.S. Environmental Protection Agency (EPA) and private foundations. UC's Linda Levin, PhD and Columbia University Mailman School's Julie Herbstman, PhD, and Deliang Tang, MD, DrPH, were also co-authors of the study.

In Flurry Of Studies, Researcher Details Role Of Apples In Inhibiting Breast Cancer

Six studies published in the past year by a Cornell researcher add to growing evidence that an apple a day -- as well as daily helpings of other fruits and vegetables -- can help keep the breast-cancer doctor away.In one of his recent papers, published in the Journal of Agricultural and Food Chemistry (57:1), Rui Hai Liu, Cornell associate professor of food science and a member of Cornell's Institute for Comparative and Environmental Toxicology, reports that fresh apple extracts significantly inhibited the size of mammary tumors in rats -- and the more extracts they were given, the greater the inhibition.

"We not only observed that the treated animals had fewer tumors, but the tumors were smaller, less malignant and grew more slowly compared with the tumors in the untreated rats," said Liu, pointing out that the study confirmed the findings of his preliminary study in rats published in 2007.

In his latest study, for example, he found that a type of adenocarcinoma -- a highly malignant tumor and the main cause of death of breast-cancer patients, as well as of animals with mammary cancer -- was evident in 81 percent of tumors in the control animals. However, it developed in only 57 percent, 50 percent and 23 percent of the rats fed low, middle and high doses of apple extracts (the equivalent of one, three and six apples a day in humans), respectively, during the 24-week study.

"That reflects potent anti-proliferative [rapid decrease] activity," said Liu.

The studies highlight the important role of phytochemicals, known as phenolics or flavonoids, found in apples and other fruits and vegetables. Of the top 25 fruits consumed in the United States, Liu reported in the same journal (56:18) that apples provide 33 percent of the phenolics that Americans consume annually.

In a study of apple peel published in the same journal (56:21), Liu reported on a variety of new phenolic compounds that he discovered that also have "potent antioxidant and anti-proliferative activities" on tumors. And in yet another study in the same journal (56:24), he reported on his discovery of the specific modulation effects that apple extracts have on cell cycle machinery. Recently, Liu's group also reported the finding that apple phytochemicals inhibit an important inflammation pathway (NFkB) in human breast cancer cells.

Breast cancer is the most frequently diagnosed invasive cancer and the second leading cause of cancer deaths in women in the United States, said Liu.

"These studies add to the growing evidence that increased consumption of fruits and vegetables, including apples, would provide consumers with more phenolics, which are proving to have important health benefits. I would encourage consumers to eat more and a wide variety of fruits and vegetables daily."

The studies were supported, in part, by the American Institute for Cancer Research, the Ngan Foundation and the U.S. Apple Association.