Yonsei Med J.  2009 Feb;50(1):105-111. 10.3349/ymj.2009.50.1.105.

TGF-beta Mediated Epithelial-Mesenchymal Transition in Autosomal Dominant Polycystic Kidney Disease

• Chea SW
• Lee KB

• KMID: 1782975
• DOI: http://doi.org/10.3349/ymj.2009.50.1.105

Abstract

PURPOSE
Recent studies have showed that epithelial-mesenchymal transition (EMT) is a key process of glomerular and tubulointerstitial pathology in many chronic kidney diseases. However, there are no data of EMT in humane autosomal dominant polycystic kidney disease (ADPKD).
PATIENTS AND METHODS
ADPKD kidneys (N = 5) with end stage renal disease (ESRD) and control kidneys (N = 4) were analyzed immnunohistochemically. We evaluated alpha-SMA, E-cadherin, vimentin, TGF-beta1 and Smad 2/3 expression in ADPKD and compared them with those in control kidney. These immunohistochemical findings were quantitatively analyzed by computer-assisted image analyzer and positive tubules (%).
RESULTS
There were severe interstitial fibrosis and proliferation of alpha-SMA+ myofibroblasts in ADPKD. Cystic tubular epithelial cells in ADPKD lost epithelial marker (E-cadherin) and expressed mesenchymal markers (alpha-SMA, vimentin). There were significant increases of alpha-SMA (34.3 +/- 11.7% vs 0.9 +/- 1.5%), vimentin (19.9 +/- 3.9% vs 3.3 +/- 1.4%), TGF-beta1 (5.42 +/- 2.83% vs 0%) and Smad 2/3 (3.4 +/- 1.7% vs 0.7 +/- 0.6%) in ADPKD kidneys compared with control kidneys evidenced by computer-assisted image analyzer. When we analyze the positive tubules (%), the results were the same as computer-assisted image analyzer.
CONCLUSION
Our results showed that the end stage of ADPKD is associated with TGF-beta, Smad 2/3 and markers of EMT. It suggests that TGF-beta mediated EMT has a role in progression of ADPKD.

Keyword

Epithelial mesenchymal transition; antosomal dominant polycystic kidney disease

MeSH Terms

Aged
Biological Markers/metabolism
Cell Division
Disease Progression
Epithelial Cells/*pathology
Female
Fibrosis
Humans
Kidney Glomerulus/pathology
Kidney Tubules/pathology
Male
Mesoderm/*pathology
Middle Aged
Polycystic Kidney, Autosomal Dominant/*metabolism/*pathology
Transforming Growth Factor beta/*metabolism

Figure

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  Fig. 1 Immunohistochemical staining for α-SMA. α-SMA is a mesenchymal and myofibroblast marker. In normal kidneys, α-SMA was negative for tubular epithelial cells; there were a few positive myofibroblasts in the interstitium (A, × 200). In ADPKD kidneys, the stromal cells were diffusely positive (B, × 200), and occasional epithelial cells in the dilated cysts were positive (C and D, × 400, arrows). α-SMA, α-smooth muscle actin; ADPKD, autosomal dominant polycystic kidney disease.

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  Fig. 2 Immunohistochemical staining for E-cadherin. E-cadherin is an epithelial cell marker. E-cadherin was widely expressed in distal tubular and collecting duct epithelial cells of normal kidneys (A, × 200). In ADPKD kidneys, the E-cadherin expression pattern was heterogeneous; there were portions in cystic epithelial cells of large renal cysts with decreased expression (B, × 200, C and D, × 400). ADPKD, autosomal dominant kidney disease.

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  Fig. 3 Immunohistochemical staining for vimentin. Vimentin is a mesenchymal cell marker. Vimentin was positive in a few tubular epithelial cells of normal kidneys (A and B, × 200). In ADPKD kidneys, vimentin expression was increased in the stromal and cystic epithelial cells (C, × 200 and D, × 400). ADPKD, autosomal dominant kidney disease.

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  Fig. 4 Immunohistochemical staining for TGF-β1. TGF-β1 was negative in the normal kidneys (A, × 200 and B, × 400). In ADPKD kidneys, TGF-β1 was upregulated in cystic epithelial cells (C and D, × 400). TGF-β1, transforming growth factor-β1; ADPKD, autosomal dominant kidney disease.

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  Fig. 5 Immunohistochemical staining for Smad 2/3. Smad 2/3 showed sparse weakly positive cells in the normal kidneys (A, × 200 and B, × 400). The cystic epithelial cells showed moderately positive reactions in ADPKD kidneys (C and D, × 400). ADPKD, autosomal dominant kidney disease.

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