[HTML][HTML] Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure

A Ortiz, C Lorz, MP Catalán, TM Danoff, Y Yamasaki… - Kidney international, 2000 - Elsevier
A Ortiz, C Lorz, MP Catalán, TM Danoff, Y Yamasaki, J Egido, EG Neilson
Kidney international, 2000Elsevier
Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or
following acute renal failure. 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 …
Expression of apoptosis regulatory proteins in tubular epithelium stressed in culture or following acute renal failure.
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-α), 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-α-induced apoptosis (P < 0.05). The latter was prevented by enforced overexpression of BclxL (P < 0.01). TNF-α 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-α 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.
Elsevier