Renal fibrosis and angiogenesis
Ann Chen1, Shuk-Man Ka2, Yee-Fun Su1, Hui-Yao Lan3 and Yeukuang Hwu4
1
Department of Pathology, Tri-Service General Hospital, 2Graduate Institute of
Aerospace and Undersea Sciences, National Defense Medical Center; 3Department of
Medicine and Therapeutics, and Li-Ka Shing Institute of Health Sciences, the Chinese
University of Hong Kong; 4Institute of Physics, Academia Sinica, Taiwan, Republic of
China
Chronic kidney disease, characterized by progressive renal injury, is a leading public
health problem worldwide because of its high rates of morbidity and mortality. The
development of renal fibrosis is the hallmark of progressive renal injury. In chronic
kidney disease, including diabetic and hypertensive nephropathy, elevated serum and
urinary levels of transforming growth factor-beta1 (TGF-β1) have been shown to
correlate with progressive renal injury. It is now well recognized that TGF-β1 exerts
pathological effects by activating two downstream mediators, Smad2 and Smad3.
This can be easily identified by phosphorylated Smad2/3 nuclear translocation within
the diseased renal tissues using a conventional immunohistochemistry. Indeed, we
found that progressive renal fibrosis is associated with local upregulation of TGF-β1
and a marked activation of Smad signaling as demonstrated by nuclear location of
phosphor-Smad2/3. These observations are also confirmed in a number of animal
models including obstructive nephropathy, hypertensive kidney disease, and diabetic
nephropathy. The functional role of TGF-β/Smad signaling in progressive renal
injury is further confirmed by the ability of blocking Smad2/3, to attenuate renal
injury. On the other hand, TGF-β1 has been shown to induce proangiogenic and
antiangiogenic factors in terms of angiogenesis which plays a key role in numerous
disease processes. One of the most important angiogenic factors is vascular
endothelial growth factor (VEGF), whereas thrombospondin-1 (TSP-1) is a major
antiangiogenic factor. Growing evidence has shown that VEGF and TSP-1 is
regulated by TGF-β1 via parallel but distinct Smad pathways.
Key words: Chronic kidney disease; fibrosis; transforming growth factor- β 1;
Smad2/3; angiogenesis; vascular endothelial growth factor; thrombospondin-1