DNA-SYNTHESIS IS DISSOCIATED FROM THE IMMEDIATE-EARLY GENE RESPONSE IN THE POSTISCHEMIC KIDNEY

The response of the kidney to ischemic injury includes increased DNA s ynthesis, which is preceded by rapid and brief expression of the c-fos proto-oncogene. While the timing of these two events would suggest th at c-Fos participates in an immediate-early gene program leading to pr oliferation, no direct test of this hypothesis exists. The purpose of these studies was (1) to determine whether c-fos is expressed as part of a typical immediate-early (IE) gene response, which would require c o-expression of c-jun and sensitivity to cycloheximide, and (2) to det ermine whether the cells expressing c-Fos are the same as those underg oing DNA synthesis. Northern analysis was performed on renal mRNA at d ifferent times following release of a 50 minute period of renal hilar clamping. c-jun and c-fos mRNA were rapidly and briefly expressed foll owing renal ischemia and their expression was superinduced by cyclohex imide in a manner typical of an immediate-early gene response. H-3-thy midine autoradiography performed on semi-thin sections from intravascu larly perfusion fixed kidneys 24 hours following induction of ischemia showed labeled nuclei in cells lining the damaged proximal tubules of the outer stripe of the outer medulla, as well as proximal tubules in the cortex and interstitial cells throughout the kidney. However, imm unohistochemical localization of c-Fos and c-Jun protein occurred pred ominantly in nuclei of the thick ascending limb, distal tubule and col lecting duct cells. The studies demonstrate that c-fos and c-jun are e xpressed following renal ischemia as a typical immediate-early gene re sponse, but they are expressed in cells that do not enter the cell cyc le. The failure of the cells to enter the cell cycle may depend on the co-expression of jun-B and jun-D, which suppress the mitogenic activi ty of c-Jun in other cells. The data suggest that the IE response foll owing renal ischemia is part of the stress response, which is antiprol iferative rather than proliferative. The role of the stress response d uring renal ischemia and the fate of the cells undergoing it are unkno wn.