of the Max - MDC

Hypertension, Vascular
Disease, Genetics, and
Nephrology
Friedrich C. Luft
The Department of Nephrology/Hypertension/Clinical Pharmacology, headed by Friedrich C. Luft, encompasses
several research groups (Jens Jordan, Clinical Research Center; Wolf-Hagen Schunck, Eicosanoids; Dominik N.
Müller, Helmholtz Fellow; Kai Schmidt-Ott, Emmy Noether Fellow) that are reported elsewhere in the MDC Research
Report. Friedrich C. Luft’s group is interested in molecular and genetic mechanisms contributing to blood pressure
regulation, cardiovascular, and renal diseases. Ralph Kettritz is pursuing mechanisms responsible for proteinase-3
(PR3) and myeloperoxidase (MPO) antibody-induced vasculitis. The neutrophil is the key cell in these diseases. He
and his team recently showed that the major hisocompatibility complex HLA region largely explains genetic variance
on PR3, that NB1 mediates surface expression of PR3, and that platelets can transfer receptors onto neutrophils.
Sylvia Bähring is pursuing the molecular genetics of autosomal-dominant brachydactyly and hypertension. She is
elucidating a novel gene probably encoding for a micro-RNA. Volkmar Gross pursues blood pressure regulation and
sympathetic nerve activity in several gene-deleted mouse models, and thereby utilizes state-of-the-art physiological
techniques adapted to the 25 g conscious mouse. Anette Fiebeler uncovered hitherto fore unknown glucocorticoidmediated
signaling via the mineralocorticoid receptor in vascular cells.
Vasculitis
ANCA-associated vasculitides are a common cause of rapidly
progressive glomerulonephritis that are influenced by
genetic variance. Neutrophil membrane expression of the
ANCA antigen proteinase 3 (PR3) is pathogenically important.
The percentage of membrane PR3-positive neutrophils
is genetically determined. The Kettritz laboratory studied
pairs of HLA-matched siblings, typed for their percentage of
membrane PR3-positive neutrophils. The group showed that
a 34 HLA-antigen cluster predicted a large fraction of the
membrane PR3 phenotype in patients and control subjects.
In their cohort, the Kettritz group found an association of
Wegener’s granulomatosis with the same group of HLA antigens
that predicted for membrane PR3 percentage and a
similar correlation with clinical parameters at initial presentation.
Their data suggest that a complex interaction of the
entire HLA system is responsible for the genetic influence
on membrane PR3 percentage and Wegener’s granulomatosis.
Sibylle von Vietinghoff used neutrophils from healthy
donors, patients with vasculitis, and neutrophilic differentiated
stem cells. She found that mPR3 display was restricted
to cells expressing neutrophil glycoprotein NB1, a glycosylphosphatidylinositol
(GPI)-linked surface receptor. The
mPR3 expression was decreased by enzymatic removal of
GPI anchors from cell membranes and was absent in a
patient with paroxysmal nocturnal hemoglobinuria. PR3 and
NB1 co-immunoprecipitated from and colocalized on the
neutrophil plasma membrane. Transfection with NB1
resulted in specific PR3 surface binding in different cell
types. The Kettritz laboratory concluded that PR3 membrane
expression on neutrophils is mediated by the NB1 receptor.
The group also pursues novel mouse vasculitis models
(shown). The Kettritz laboratory has also contributed to
receptor transfer between platelets and neutrophils, as
well as to our knowledge regarding the meaning of “fever”
in their studies of neutrophil function at varying temperatures.
Molecular genetics
Sylvia Bähring is spearheading the investigation of
autosomal-dominant hypertension with brachydactyly, a
Mendelian cause of hypertension and stroke, for over a
decade. The group has shown that a chromosomal
rearrangement on 12p is responsible for the syndrome.
Martin Kann narrowed the gap with a 24-BAC array and
interphase FISH in five families. Although the rearrangements
differ, a common denominator now comprises an
inversion interval of about 500 kb. No known genes reside
in the inverted interval. The expressed sequence tags (EST)
that are present are being investigated by 3’ and 5’ RACE
PCR. Thus far, the emerging gene-related structure comprises
32 exons, which are multiply spliced. Two of the exons
are never expressed in affected persons. Since open reading
frames and Kozar sequences are conspicuously absent, the
gene may not code for protein. The emerging structure
(shown) resembles a novel micro RNA.
Cardiovascular and Metabolic Disease Research 15