GENE-EXPRESSION IN NEPHROTOXIC AND ISCHEMIC ACUTE-RENAL-FAILURE

The commitment to DNA synthesis by the kidney to recovery from ischemic and nephrotoxic acute renal failure is accompanied by a pattern of gene expression that bears a striking resemblance to that exhibited by growth factor-stimulated cells in culture. Prominent among them is the expression of the immediate early genes that code for transcriptional factors that are rapidly and briefly expressed well before the onset of DNA synthesis. Other genes are activated that code for small secreted peptides. These proteins have cytokine-like activity that may be involved in the recruitment and activation of other cells that serve the regenerative response in some way. The expression of several additional genes, which are relatively kidney specific and developmentally regulated, are actually reduced during renal failure, suggesting that the commitment to DNA synthesis by the kidney may require dedifferentiation. Many different cell types participate in the increased DNA synthesis provoked by ischemic and nephrotoxic damage, including tubule cells removed from the site of greatest injury, as well as those outside of the tubule compartment, suggesting that paracrine, autocrine, and juxtacrine factors support the growth-promoting process. A prominent site of altered gene expression during acute renal failure is the thick ascending limb, which undergoes both positive and negative changes in expression and which seems to be a prominent site of reaction to nephrotoxic stimuli at the molecular level. Studying the interaction between the regulatory sequences of a select group of genes with their transactivating factors and the transduction pathways that activate them should identify the initial growth-promoting signal and the subsequent steps leading to renal regeneration. It is likely that a better understanding of these processes will lead to new strategies that can be applied to promote the full and more rapid recovery of the injured kidney.