The carnosinase 1 gene, located on human
chromosome 18, produces the protective
factor, said Barry I. Freedman, M.D., the
John H. Felts III Professor and head of the
Section on Nephrology, in an article in
Nephrology Dialysis Transplantation
published online.
“This is a major gene that appears to be
associated with development of severe
diabetic kidney disease,” he said.
The research team evaluated 858 subjects,
including diabetic patients with end-stage
kidney failure on dialysis, diabetic
patients with normal kidney function, and
healthy non-diabetic individuals. They
confirmed that a protective form of the
carnosinase 1 gene was present in greater
frequency among both healthy individuals and
diabetic subjects without kidney disease,
compared to the diabetic patients on
dialysis who more commonly had forms of the
gene that were not protective.
This discovery may lead to novel treatment
strategies in susceptible diabetic patients
to protect them from kidney failure and may
provide a marker to determine which diabetic
patients are at increased risk for future
kidney disease, Freedman said.
The carnosinase 1 gene produces an enzyme
called carnosinase. Carnosinase inactivates
the protective substance carnosine.
Carnosine appears to prevent scarring from
developing in kidney tissue and serves as a
scavenger of damaging oxygen-free radicals.
“Prior to these genetic analyses, kidney
doctors were unaware that this pathway
played an important role in diabetic kidney
disease,” Freedman said.
He added that the groups at Wake Forest and
in Germany had been looking for the gene or
genes after concluding that a region on
chromosome 18 was important in predisposing
people who have type 2 diabetes (adult onset
diabetes) to the development of severe
kidney failure. Freedman said the actions of
this gene apply to Europeans, American
whites and Arabs.
When his group repeated the analysis in
black Americans, there was no evidence that
the carnosinase pathway was involved in
their kidney failure.
“It is possible that American blacks have
different carnosine metabolism, making them
less susceptible to alterations in
carnosinase gene activity. Analyses are
currently under way,” said Freedman. “It is
also possible that an additional gene or
genes on chromosome 18 is associated with
susceptibility to end-stage kidney disease
in black Americans, and our group is
actively trying to identify them.”
Freedman said that among people who are
susceptible to kidney failure, “it will be
important to evaluate whether the
administration of carnosine or agents that
inhibit carnosinase activity will protect
diabetic individuals from the development of
progressive kidney disease.”
He said that while carnosine is available
over the counter in health food stores, it
is possible that excessive carnosinase
enzyme activity could prevent carnosine
supplementation from protecting the kidney.
As such, carnosinase blockers may prove to
be more important.
Freedman noted that Wake Forest researchers
"have one of the largest existing
collections of DNA samples from black and
white families with multiple members having
end-stage kidney disease. We have been
evaluating these families since 1991.”
Besides Freedman, the research team includes
Donald W. Bowden, Ph.D., Pamela J. Hicks,
B.S., Michele M. Sale, Ph.D., Eric F.
Pierson, M.D., Carl D. Langefield, Ph.D.,
Stephen S. Rich, Ph.D., Jianzhao Xu, B.S.,
and Caitrin McDonough, B.S., all from Wake
Forest, Bart Janssen, M.D., and Benito A.
Yard, M.D., from the Institute of Human
Genetics in Heidelberg, Germany, and Fokko
J. van der Woude from Fifth Medical
Department, University Clinic (Universitätsklinikum),
Mannheim Germany.
Wake
Forest University Baptist Medical Center is
an academic health system comprised of North
Carolina Baptist Hospital and Wake Forest
University Health Sciences, which operates
the university’s School of Medicine. The
system comprises 1,187 acute care,
psychiatric, rehabilitation and long-term
care beds and is consistently ranked as one
of “America’s Best Hospitals” by U.S.
News & World Report.
