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Raimund
Hirschberg, MD
Degree:
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Research
Focus:
The
main body of experimental work in the Hirschberg lab addresses 'mechanisms of
renal fibrogenesis'. We presently examine the role of cytokines within the
TGFβ superfamily of cysteine-knot cytokines, specifically bone
morphogenetic protein-7 (BMP7) and growth and differentiation factor-15
(GDF15). As
we found in previous years BMP7 is endogenously expressed in the kidney
(podocytes, distal nephron epithelium) and has antifibrogenic functions;
i.e., BMP7 reduces the TGFβ-induced expression of extracellular matrix
proteins and many fibrosis-regulating factors by renal epithelial cells
in-vitro and in-vivo. We showed that in tubular cells BMP7 utilizes
preferable (or exclusively) smad5 (rather than smad1) as the
receptor-activated smad substrate. The mechanisms through which BMP7 hinders
the pro-fibrogenic activities have also been unraveled in our lab, at least
in part. We found that BMP7-activated smad5 induces smad6, and the increased
level of this latter smad protein reduce the signal activity of
TGFβ-smad2/3/4 into the nucleus. Thus, BMP7 acts as a signal inhibitor
for TGFβ. Whereas
BMP7 is heavily expressed in many tissues throughout embryonic development,
its expression disappears from most organs in adult organisms. A notable
exception is the kidney, where this peptide appears to play the role of an
antifibrogenic regulator. However, its renal expression declines early in
many experimental renal diseases, before or at the onset of interstitial
renal fibrosis and chronic renal failure. This has been shown in experimental
diabetic nephropathy and unilateral obstructive nephropathy. This observation
led us to direct our experiments into two directions: First, what is the
consequence of the disappearance ob renal BMP7 in renal diseases
(specifically diabetic nephropathy); and second, what are the mechanisms
down-regulating BMP7 expression in these conditions? We
addressed the first question with studies in transgenic mice expressing the
BMP7 transgene under control of the PEPCK-promoter made diabetic. The
findings, in brief, corroborate the expected function of endogenous, renal
BMP7, namely to reduce early fibrogenic processes. The
second question is currently studied in detail. Initial findings show that
high glucose (mimicking hyperglycemia of diabetes) upregulates BMP7 promoter
activity, but it is down regulated by TGFβ. We have identified the
minimum promoter segement that is regulated by glucose and TGFβ and are
actively engaged in the identification of potential transcriptional regulators
using unbiased methods. A
second line of experiments involving GDF15 is in its infancy and findings
will be added as appropriate. In
an independent and not directly related project the laboratory examines
endothelial progenitor cells. The specific goals of this project is to
examine the hypothesis that azotemia and uremia as well as the diabetic,
hyperglycemic state injure these cells and affect their subsequent phenotype. |
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