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Apoptotic tubular cell death during acute renal allograft rejection
P C Wever1, J Aten, R J Rentenaar
1Renal Transplant Unit, University of Amsterdam, The Netherlands.
Abstract:
Tubular cells are important targets during acute renal allograft rejection and induction of apoptosis might be a mechanism of tubular cell destruction. Susceptibility to induction of apoptosis is regulated by the homologous Bcl-2 and Bax proteins. Expression of Bcl-2 and Bax is regulated by p53, which down-regulates expression of Bcl-2, while simultaneously up-regulating expression of Bax. We studied apoptotic tubular cell death in 10 renal allograft biopsies from transplant recipients with acute rejection by in situ end-labelling and the DNA-binding fluorochrome propidium iodide. Tubular expression of p53, Bcl-2 and Bax was studies by immunohistochemistry. Five renal allograft biopsies from transplant recipients with uncomplicated clinical course and histologically normal renal tissue present in nephrectomy specimens from 4 patients with renal adenocarcinoma served as control specimens. Apoptotic cells and apoptotic bodies were detected in tubular epithelia and tubular lumina in 9 out of 10 acute rejection biopsies. In control renal tissue, apoptotic cells were detected in 1 biopsy only. Compared to control renal tissue, acute renal allograft rejection was, furthermore, associated with a shift in the ratio of Bcl-2 to Bax in favour of Bax in tubular epithelia and increased expression of p53 in tubular nuclei. These observations demonstrate that apoptosis contributes in part to tubular cell destruction during acute renal allograft rejection. In accordance, the shift in the ratio of Bcl-2 to Bax in favour of Bax indicates increased susceptibility of tubular epithelia to induction of apoptosis. The expression of p53 in tubular nuclei during acute renal allograft rejection indicates the presence of damaged DNA, which can be important in initiation of part of the observed apoptosis. These findings elucidate part of the mechanisms controlling apoptotic tubular cell death during acute renal allograft rejection.
Insights
Apoptosis contributes to tubular cell destruction in acute renal allograft rejection. This is linked to increased Bax protein, decreased Bcl-2, and elevated p53 expression, indicating greater susceptibility to cell death.
Area of Science:
- Nephrology
- Immunology
- Cell Biology
Background:
- Tubular cells are key targets in acute renal allograft rejection.
- Apoptosis (programmed cell death) is a potential mechanism for tubular cell damage.
- The Bcl-2 family proteins (Bcl-2 and Bax) and p53 regulate apoptosis susceptibility.
Purpose of the Study:
- To investigate the role of apoptotic tubular cell death in acute renal allograft rejection.
- To analyze the expression of p53, Bcl-2, and Bax in rejecting renal allografts.
Main Methods:
- Studied 10 renal allograft biopsies with acute rejection.
- Used in situ end-labeling and propidium iodide for apoptosis detection.
- Examined tubular p53, Bcl-2, and Bax expression via immunohistochemistry.
Main Results:
- Apoptotic cells were found in 90% of acute rejection biopsies versus 10% in controls.
- Acute rejection showed an increased Bax to Bcl-2 ratio, favoring Bax.
- Elevated p53 expression was observed in tubular nuclei during acute rejection.
Conclusions:
- Apoptosis plays a role in tubular cell destruction during acute renal allograft rejection.
- The altered Bcl-2/Bax ratio suggests increased tubular cell apoptosis susceptibility.
- Increased p53 indicates DNA damage, potentially initiating apoptosis in rejecting allografts.