Relationship between expression of Bcl-2 genes and growth factors in ischemic acute renal failure in the rat

The promotion of cell survival and regeneration in acute renal failure (ARF ) is important for restitution of renal function. This study analyzes the t emporal and spatial relationship between expression of pro- and anti-apopto tic members of the Bcl-2 gene family (Bcl-2, Bcl-X-L, Bax) and epidermal gr owth factor (EGF), insulin-like growth factor-1 (IGF-1), and transforming g rowth factor-beta (TGF-beta), growth factors that are thought to be reparat ive in ARF. A rat model of ischemic ARF involving 30 min of bilateral renal artery occlusion followed by reperfusion for 0 to 14 d was used. Apoptosis and mitosis were quantified and qualitative assessment was made of other c ellular damage including necrosis and loss of cellular adhesion. Locality a nd level of expression of the Bcl-2 and growth factor proteins were determi ned using immunohistochemistry. Apoptosis peaked between 4 and 14 d postisc hemia in both proximal and distal tubules. Mitosis peaked at 2 d in proxima l tubules and 4 to 14 d in the distal tubules. A spatio-temporal relationsh ip was observed between anti-apoptotic Bcl-2 gene family members and growth factors after ischemia-reperfusion. In control kidneys, expression of Bcl- 2, Bcl-X-L was low in epithelium of distal tubules, Bar had low-to-moderate expression in the proximal tubule and had low expression in the distal tub ule, EGF and IGF-1 had low-to-moderate expression in the distal tubule, and TGF-beta had low expression in the proximal tubule. In contrast, within 24 h of reperfusion, distal tubules showed a marked increase in expression of Bcl-2 and a moderate increase in Bcl-X-L and Bax. Proximal tubules showed a marked increase in Bar expression and a moderate increase in Bcl-X-L. Twe nty-four hours after expression of the Bcl-2 proteins was increased, IGF-1 and EGF protein levels were increased in the distal tubule, similar to the Bcl-2 anti-apoptotic proteins, and were also detected in the adjacent proxi mal tubules, suggestive of paracrine action in these tubules. TGF-beta expr ession was moderately increased in regenerating proximal tubules, but no re lationship was seen with the pattern of expression of the Bcl-2 genes. An e xplanation of these results is that the distal tubule is adaptively resista nt to ischemic injury via promotion of survival by anti-apoptotic Bcl-2 gen es, and its survival allows expression of growth factors critical not only to the maintenance and regeneration of its own cell population (autocrine a ction), but also to the adjacent ischemia-sensitive proximal tubular cells (paracrine action).