Chronic Allograft Nephropathy: Intraepithelial Signals Generated by Transforming Growth Factor- b and Bone Morphogenetic Protein-7

Applied Immunobiology and Transplantation Research Group, The Medical School, University of Newcastle, Newcastle upon Tyne NE2 4HH, UK.
American Journal of Transplantation (Impact Factor: 5.68). 07/2006; 6(6):1367-76. DOI: 10.1111/j.1600-6143.2006.01339.x
Source: PubMed

ABSTRACT It has been suggested that TGFbeta can cause chronic allograft nephropathy by inducing epithelial to mesenchymal transition (EMT); some studies show a reverse transition can be produced by bone morphogenetic protein-7 (BMP7). The current study assessed the relative contribution of signals generated within tubular epithelial cells by TGFbeta and BMP7 in normal kidney and after transplantation. Epithelial cells in normal human kidneys expressed phosphorylated forms of both Smad2/3 and Smad1/5/8 within their nuclei; cell culture experiments showed that these signaling molecules were generated in response to TGFbeta and BMP7, respectively. Phospho(p)-Smad2/3 was expressed at increased levels by tubular epithelial cells during acute renal allograft rejection and chronic allograft nephropathy but pSmad1/5/8 was expressed at very low levels; this staining profile was associated with induction of the EMT marker, S100A4. Further in vitro experiments demonstrated that this pattern of Smad signaling was a consequence of the stimulation of tubular epithelial cells with TGFbeta in the absence of BMP7. Importantly, addition of BMP7 to TGFbeta-stimulated cells enhanced the expression of pSmad1/5/8 and reduced expression of S100A4. These results suggest that exogenous BMP7 could restore the homeostatic balance of pSmad signaling found in normal kidneys, thereby preventing or reversing the development of chronic allograft nephropathy.

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Available from: Helen Robertson, Oct 30, 2014
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    • "However, TGF-β also activates the noncanonical, SMAD-independent pathways such as Ras/rho and MAPK, NF-kB, or PI3kinase/AKT pathway. Receptor-activated SMAD protein complexes translocate within the nucleus and initiate transcription of target genes [37–39]. "
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    ABSTRACT: Renal transplantation (RT) is the best option for patients with end-stage renal disease, but the half-life is limited to a decade due to progressive deterioration of renal function and transplant failure from chronic allograft nephropathy (CAN), which is the leading cause of transplant loss. Extensive research has been done to understand the pathogenesis, the biological pathways of fibrogenesis and potential therapeutic targets for the prevention and treatment of CAN. Despite the advancements in the immunosuppressive agents and patient care, CAN continues to remain an unresolved problem in renal transplantation. The aim of this paper is to undertake a comprehensive review of the literature on the pathogenesis, biological pathways of RT fibrogenesis and potential therapeutic targets for the prevention and therapy of CAN.
    BioMed Research International 06/2014; 1-13. DOI:10.1155/2014/482438 · 3.17 Impact Factor
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    • "EMT is another important process affecting the population of interstitial fibroblasts which lose their epithelial phenotype and show the progressive development of a mesenchymal phenotype that leads to TEC damage and fibrosis in the kidney [11]. Many studies have demonstrated that TGF-í µí»½ promotes renal fibrosis through EMT by activation of Smad2/3 [12] [13] [14] and was counteracted with BMP-7 by motivation of Smad1/5/8 to maintain the epithelial phenotype of TECs [15] [16]. The expression of the mesenchymal phenotype in TECs and fibroblasts using S100A4 as a marker has been observed in many kidney diseases [17] [18]. "
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    ABSTRACT: This study aims to investigate the renoprotective effect of recombinant human erythropoietin (rhEPO) treatment could preserve tubular epithelial cell regeneration and ameliorate renal fibrosis by dual inhibition of stress-induced senescence and EMT in unilateral ureteric obstruction (UUO) mouse model. UUO or sham-operated mice were randomly assigned to receive rhEPO or vehicle treatment and were sacrificed on days 3, 7, and 14. Kidney specimens were fixed for histopathological and immunohistochemical study. The expression of S100A4, TGF- β 1, BMP-7, Smad2/3, Smad1/5/8, and p16(INK4a) was determined by western blot and real-time RT-PCR. Vehicle treated UUO mice had increased tubular atrophy and interstitial fibrosis within 3 to 14 days. An increase in TGF- β 1, Smad2/3, S100A4, and p16(INK4a) expression and a decrease in BMP-7 and Smad1/5/8 expression were observed in the obstructed kidneys. p16(INK4a) was positively correlated with TGF- β 1/Smad2/3 and negatively correlated with BMP-7/Smad1/5/8 in UUO mice. rhEPO treatment significantly suppressed the upregulation of TGF- β , Smad2/3, S100A4, and p16(INK4a) and preserved the downregulation of BMP-7 and Smad1/5/8, resulting in markedly reduced TA/IF compared to the vehicle treated mice. The renoprotective effects of rhEPO could ameliorate renal TA/IF by modulating senescence and EMT which could be a part of therapeutic option in patients with chronic kidney disease.
    11/2013; 2013(1):308130. DOI:10.1155/2013/308130
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    ABSTRACT: Chronic allograft nephropathy (CAN) is a leading cause of kidney graft failure following transplantation. Its causes are complex and include both immunological and nonimmunological factors. Here we have studied the development of CAN in a mouse model of kidney transplantation comparing isografts and allografts. Unlike the normal histology and normal serum creatinine of the uninephrectomized, nonrejecting isografted mice (0.219 +/- 0.024 mg/dL), allografted mice demonstrated severe renal dysfunction (mean serum creatinine 0.519 +/- 0.061 mg/dL; p < 0.005) with progressive inflammation and fibrosis of the kidney. These animals also showed an increased expression of connective tissue growth factor (CTGF), both systemically and within the graft. CTGF was highly expressed in tubuloepithelial cells of allografts, along with alpha-smooth muscle actin, a marker of myofibroblasts, and transcriptionally associated with other markers of fibrosis. In vitro studies of tubular epithelium indicate that CTGF is capable of inducing EMT, independent of TGF-beta. Finally, in human transplant recipients, serum and urine CTGF levels are significantly elevated compared to naïve individuals. Urinary levels correlated with the histological presence of CAN. These studies suggest a critical role of CTGF in graft fibrogenesis, for both mouse and man. Thus, CTGF has potential as a biomarker of CAN, and also a therapeutic target in managing graft fibrosis.
    American Journal of Transplantation 11/2006; 6(10):2292-306. DOI:10.1111/j.1600-6143.2006.01493.x · 5.68 Impact Factor
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