BACKGROUND: While tubular cell death is a characteristic of acute renal failure (ARF), the molecular mechanisms that modulate this cell death are unclear. Cell fate in acute renal failure hinges on a balance of survival and mortality factors in a changing environment. We further explored this issue by studying selected cell death-related proteins in experimental renal failure. METHOD: The expression of genes that promote (c-myc, Bax, BclxS) or protect (Bcl2, BclxL) from cell death was studied by Northern blot, Western blot, and immunohistochemistry in murine kidneys following ARF induced by folic acid or in renal tubular epithelial cells (MCT) stressed in culture. RESULTS: Renal mRNA levels encoding for c-myc and BclxL were elevated in ARF while the Bcl2/Bax ratio was decreased (Bcl2 decreased and Bax increased; P < 0.05). Protein levels of BclxL increased and Bcl2 protein decreased. Expression of tumor necrosis factor (TNF-alpha), a mediator of ARF, was also increased. Immunohistochemistry further demonstrated that BclxL was increased in some tubuli and absent in others, while Bcl2 expression decreased diffusely. Bax staining was also patchy among tubuli and individual cells in the tubular wall and lumen. As a relative deficit of survival factors is present in ARF, MCT epithelium were deprived of serum survival factors. This resulted in apoptosis, decreased Bcl2/Bax and BclxL/Bax ratios (P < 0.05) and sensitization to TNF-alpha-induced apoptosis (P < 0.05). The latter was prevented by enforced overexpression of BclxL (P < 0.01). TNF-alpha increased the mRNA levels encoding for c-myc and decreased BclxL expression. Neither MCT cells nor the kidney expressed BclxS. CONCLUSIONS: A relative deficit of survival factors likely contributes to changes in levels of BclxL and Bax in ARF. These deficits predispose to cell death induced by persistent lethal factors such as TNF-alpha that is increased in ARF and a potential source of increased c-myc, a downstream facilitator of cell death. These findings implicate members of the Bcl2 family of proteins as regulators of tubular cell death in ARF and single them out as potential therapeutic targets.
BACKGROUND: While tubular cell death is a characteristic of acute renal failure (ARF), the molecular mechanisms that modulate this cell death are unclear. Cell fate in acute renal failure hinges on a balance of survival and mortality factors in a changing environment. We further explored this issue by studying selected cell death-related proteins in experimental renal failure. METHOD: The expression of genes that promote (c-myc, Bax, BclxS) or protect (Bcl2, BclxL) from cell death was studied by Northern blot, Western blot, and immunohistochemistry in murine kidneys following ARF induced by folic acid or in renal tubular epithelial cells (MCT) stressed in culture. RESULTS: Renal mRNA levels encoding for c-myc and BclxL were elevated in ARF while the Bcl2/Bax ratio was decreased (Bcl2 decreased and Bax increased; P < 0.05). Protein levels of BclxL increased and Bcl2 protein decreased. Expression of tumor necrosis factor (TNF-alpha), a mediator of ARF, was also increased. Immunohistochemistry further demonstrated that BclxL was increased in some tubuli and absent in others, while Bcl2 expression decreased diffusely. Bax staining was also patchy among tubuli and individual cells in the tubular wall and lumen. As a relative deficit of survival factors is present in ARF, MCT epithelium were deprived of serum survival factors. This resulted in apoptosis, decreased Bcl2/Bax and BclxL/Bax ratios (P < 0.05) and sensitization to TNF-alpha-induced apoptosis (P < 0.05). The latter was prevented by enforced overexpression of BclxL (P < 0.01). TNF-alpha increased the mRNA levels encoding for c-myc and decreased BclxL expression. Neither MCT cells nor the kidney expressed BclxS. CONCLUSIONS: A relative deficit of survival factors likely contributes to changes in levels of BclxL and Bax in ARF. These deficits predispose to cell death induced by persistent lethal factors such as TNF-alpha that is increased in ARF and a potential source of increased c-myc, a downstream facilitator of cell death. These findings implicate members of the Bcl2 family of proteins as regulators of tubular cell death in ARF and single them out as potential therapeutic targets.
Authors: Maria Dolores Sanchez-Niño; Ana Belen Sanz; Corina Lorz; Andrea Gnirke; Maria Pia Rastaldi; Viji Nair; Jesus Egido; Marta Ruiz-Ortega; Matthias Kretzler; Alberto Ortiz Journal: J Am Soc Nephrol Date: 2010-01-28 Impact factor: 10.121
Authors: Juan A Moreno; Maria C Izquierdo; Maria D Sanchez-Niño; Beatriz Suárez-Alvarez; Carlos Lopez-Larrea; Aniela Jakubowski; Julia Blanco; Rafael Ramirez; Rafael Selgas; Marta Ruiz-Ortega; Jesus Egido; Alberto Ortiz; Ana B Sanz Journal: J Am Soc Nephrol Date: 2011-06-30 Impact factor: 10.121
Authors: Corina Lorz; Alberto Benito-Martín; Anissa Boucherot; Alvaro C Ucero; Maria Pia Rastaldi; Anna Henger; Silvia Armelloni; Beatriz Santamaría; Celine C Berthier; Matthias Kretzler; Jesus Egido; Alberto Ortiz Journal: J Am Soc Nephrol Date: 2008-02-20 Impact factor: 10.121
Authors: Ana B Sanz; Maria D Sanchez-Niño; Maria C Izquierdo; Aniela Jakubowski; Pilar Justo; Luis M Blanco-Colio; Marta Ruiz-Ortega; Rafael Selgas; Jesús Egido; Alberto Ortiz Journal: PLoS One Date: 2010-01-29 Impact factor: 3.240
Authors: Ana Belen Sanz; Pilar Justo; Maria Dolores Sanchez-Niño; Luis Miguel Blanco-Colio; Jeffrey A Winkles; Matthias Kreztler; Aniela Jakubowski; Julia Blanco; Jesús Egido; Marta Ruiz-Ortega; Alberto Ortiz Journal: J Am Soc Nephrol Date: 2008-01-30 Impact factor: 10.121