Proteinuria & EMT

Proteinuria

Recent discoveries have shed light on mechanisms by which CTGF plays important roles in multiple diseases and provide further validation of CTGF as a therapeutic target. One such discovery is related to the role of CTGF in proteinuria (abnormally high amounts of protein in the urine due to impairment of the kidney filtration barrier) and progression of renal disease. Proteinuria is an early manifestation of progressive renal diseases, such as diabetic kidney disease (DKD) and focal segmental glomerulosclerosis (FSGS).

CTGF is implicated in proteinuria due to its role in dysregulation of processes such as extracellular matrix deposition, tissue remodeling, cell adhesion, cell migration and vascular permeability, leading to scarring of the kidney and leakage of proteins from the blood into the urine. CTGF has been shown to compromise cellular architecture and survival of specialized kidney cells called podocytes, which are key components of the kidney filtration barrier, leading to exacerbation of proteinuria in an animal model of DKD.1  Podocyte loss and injury are observed in the early stages of human kidney disease. CTGF has also been shown to adversely affect adhesion of cells to the glomerular basement membrane (GBM),2, 3  one of the layers through which filtration occurs, which could lead to worsened proteinuria.

Similarly, damage to the endothelial cells, which line the blood vessels of the glomerular capillaries, can also result in proteinuria. CTGF may regulate endothelial cell survival or permeability through its effects on bioavailability of vascular endothelial growth factor (VEGF).4, 5  VEGF is produced by podocytes and is an important survival factor for glomerular endothelial cells.

Epithelial to Mesenchymal Transition (EMT)

In addition to its effects on kidney filtration function, CTGF drives excessive production of extracellular matrix through its effects on fibroblasts and epithelial to mesenchymal transition (EMT). EMT results in the conversion of a functional epithelial cell (e.g., lung airway or kidney tubule cell) to a myofibroblast cell, which has a primary role of producing scar tissue. Fibroblasts play a normal role in wound healing; however, when the insult is prolonged, severe, or for unknown reasons, the balance between growth factors is disrupted such that the signal, e.g., CTGF level, remains elevated, persistent and pathological fibrosis results. Without intervention, the systems are tasked to converting functional into non-functional tissue.

The conversion of normal epithelial cells to myofibroblasts is thought to be a final common pathway not only in renal diseases6-10 but also in other organ fibroses such as those found in the liver and heart.11  In the case of the heart, endothelial cells undergo a related conversion process (endothelial to mesenchymal cell transition) to generate matrix-producing cells.

EMT also occurs during some late stage tumorigenesis; in this case, the process leads to the generation of invasive tumor cells which migrate into the surrounding tissue, penetrate the endothelial layer of the blood vessels and travel to secondary organ sites to form metastases.

Thus, CTGF’s role in stimulating EMT may provide a common mechanism for its effects in both organ fibrosis and tumorigenesis. EMT is thought to be a key problem to finding effective therapies for diseases such as DKD and idiopathic pulmonary fibrosis. Blocking CTGF activity may provide an effective way to mitigate EMT and resulting pathologies.

References

  1. Yokoi H, et al. Overexpression of connective tissue growth factor in podocytes worsens diabetic nephropathy in mice. Kidney Int. 2008 Feb;73(4):446-55.
  2. Guha M, et al. Specific down-regulation of connective tissue growth factor attenuates progression of nephropathy in mouse models of type 1 and type 2 diabetes. FASEB J. 2007 Oct;21(12):3355-68
  3. Nguyen TQ, et al. (2008) CTGF inhibits BMP-7 signaling in diabetic nephropathy. J Am Soc Nephrol. 2008 Jul 16. [Epub ahead of print]
  4. Inoki, I, et al. Connective tissue growth factor binds vascular endothelial growth factor (VEGF) and inhibits VEGF-induced angiogenesis. FASEB J. 2002 Feb;16(2):219-21
  5. Hashimoto, G et al. Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. J Biol Chem. 2002 Sep 27;277(39):36288-95
  6. Wahab, NA and Mason, RM. A critical look at growth factors and epithelial-to-mesenchymal transition in the adult kidney. Interrelationships between growth factors that regulate EMT in the adult kidney. Nephron Exp Nephrol. 2006;104(4):e129-34.
  7. Burns WC, et al. The role of tubular epithelial-mesenchymal transition in progressive kidney disease. Cells Tissues Organs. 2007;185(1-3):222-31. Review.
  8. Burns WC, et al. Connective tissue growth factor plays an important role in advanced glycation end product-induced tubular epithelial-to-mesenchymal transition: implications for diabetic renal disease. J Am Soc Nephrol. 2006 Sep;17(9):2484-94.
  9. Liu BC, et al. Role of connective tissue growth factor (CTGF) module 4 in regulating epithelial mesenchymal transition (EMT) in HK-2 cells.Clin Chim Acta. 2006 Nov;373(1-2):144-50
  10. Shi, Y et al. Homologous peptide of connective tissue growth factor ameliorates epithelial to mesenchymal transition of tubular epithelial cells. Cytokine. 2006 Oct;36(1-2):35-44.
  11. Zeisberg EM, et al. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med. 2007 Aug;13(8):952-61.
   

 
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