quinta-feira, 24 de janeiro de 2008

Trombospondina-1 é um ativador endógeno de TGF beta em nefropatia experimental in vivo


Thrombospondin-1 Is an Endogenous Activator of TGF-
in Experimental Diabetic Nephropathy In Vivo

Christoph Daniel,1 Kathrin Schaub,1 Kerstin Amann,2 Jack Lawler,3 and Christian Hugo1

OBJECTIVE—Transforming growth factor- (TGF-), the central
cytokine responsible for the development of diabetic nephropathy,
is usually secreted as a latent procytokine complex
that has to be activated before it can bind to its receptors. Recent
studies by our group demonstrated that thrombospondin-1
(TSP-1) is the major activator of latent TGF- in experimental
glomerulonephritis in the rat, but its role in diabetic nephropathy
in vivo is unknown.

RESEARCH DESIGN AND METHODS—Type 1 diabetes was
induced in wild-type (n 27) and TSP-1–deficient mice (n 36)
via streptozotocin injection, and diabetic nephropathy was investigated
after 7, 9.5, and 20 weeks. Renal histology, TGF-
activation, matrix accumulation, and inflammation were assessed
by immunohistology. Expression of fibronectin and
TGF- was evaluated using real-time PCR. Furthermore, functional
parameters were examined.

RESULTS—In TSP-1–deficient compared with wild-type mice,
the amount of active TGF- within glomeruli was significantly
lower, as indicated by staining with specific antibodies against
active TGF- or the TGF- signaling molecule phospho-smad2/3
or the typical TGF- target gene product plasminogen activator
inhibitor-1. In contrast, the amount of glomerular total TGF-
remained unchanged. The development of diabetic nephropathy
was attenuated in TSP-1–deficient mice as demonstrated by a
significant reduction of glomerulosclerosis, glomerular matrix
accumulation, podocyte injury, renal infiltration with inflammatory
cells, and renal functional parameters.

CONCLUSIONS—We conclude that TSP-1 is an important activator
of TGF- in diabetic nephropathy in vivo. TSP-1–blocking
therapies may be considered a promising future treatment option
for diabetic nephropathy.
Diabetes 56:2982–2989, 2007

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