The beneficial impact of D3 vitamin on the decline of rejection, epithelial-mesenchymal transition (EMT), and interstitial fibrosis among pediatric renal transplant patients
Eda Yilmaz Akcay1, B. Handan Ozdemir1, Esra Baskin2, F. Nurhan Ozdemir3, Mehmet Haberal4.
1Department of Pathology, Baskent University, Ankara, Turkey; 2Department of Pediatric Nephrology, Baskent University, Ankara, Turkey; 3Department of Nephrology, Baskent University, Ankara, Turkey; 4Department of General Surgery, Division of Transplantation, Baskent University, Ankara, Turkey
Introduction: Vitamin D3 is known to prevent T-cell proliferation and inhibit the production of TNF-α. Vitamin D3 also has a critical role in reorganizing the cytoskeletal of the cells and E-cadherin (Ecad) expression necessary for maintaining the epithelial state. Ecad downregulation is considered a hallmark of EMT. We aimed to understand the role of D3 in the development of acute rejection (AR), EMT, and interstitial fibrosis (IF).
Method: Of 51 cases, 24 were treated with D3 (Group D), and 27 did not (Group C). The intensity of interstitial macrophage and lymphocyte infiltration graded in the first indication biopsies. The α-SMA and paxillin expression on tubules were evaluated to detect EMT development. Additionally, tubular TGF-β, TNF-α, and Ecad expression were studied. Follow-up biopsies were analyzed for the development of IF during 18 and 24 months after transplant.
Results: The development of AR and IF during 18 and 24 months after transplant was found lower in Group D patients compared to Group C patients (p<0.001). Patients in Group D showed higher degrees of tubular Ecad expression than Group C (p<0.001). Tubular, α-SMA, paxillin, TGF-β, and TNF-α were found significantly lower in Group D than Group A (p<0.001). Tubular α-SMA, paxillin, TNF-α, and TGF-β expression positively correlated with the IF development (p<0.001). The degree of inflammatory cells showed a positive correlation with the tubular α-SMA, paxillin, TNF-α, and TGF-β expression (p<0.01). In contrast, they showed a negative correlation with E-cad expression (p<0.01). Tubular E-cad expression was negatively associated with the IF, α-SMA, paxillin, TNF-α, and TGF-β expression (p<0.001). The overall -5 and 10-year graft survival was 91% and 87 % for Group D, 70% and 63% for Group C, respectively (p<0.05).
Conclusion: With increasing degree of inflammation, TNF-α and TGF-β, the activation of EMT and therefore the occurrence of IF was found higher in Group C cases who had increased α-SMA and paxillin expression with Ecad downregulation. Contrarily, patients in Group D had a lower incidence of AR, EMT, IF, and favorable graft prognosis. Thus, D3 therapy is beneficial in renal transplant patients with its antifibrotic and immune modulator properties.
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