EXPRESSION OF CYTOKINE-LIKE GENES JE AND KC IS INCREASED DURING RENAL ISCHEMIA

Both mitogenic and inflammatory phenomena accompany the renal response to ischemic injury. Previous studies have shown that several nuclear-binding members of the immediate early genes are prominently expressed after renal ischemia and may underlie the mitogenic response to such injury. We now report on the expression of JE and KC, other growth-factor-responsive genes that code for small secreted glycoproteins with cytokine-like properties, which may play a role in inflammation. The expression of the immediate early genes JE and KC was determined in rat kidney tissue at varying time points after release of a 50-min period of bilateral renal hilar clamping. Relative levels of mRNA for JE and KC were analyzed by Northern blot analysis of cortical and outer stripe mRNA. KC mRNA rose rapidly to peak values at 1 h and returned toward low baseline levels by 24 h after release of the hilar clamp. By contrast, JE mRNA reached peak levels later and remained elevated for at least 96 h after ischemia. JE antigen was localized immunocytochemically to the apical regions of the cortical and medullary thick ascending limbs as well as in the lumen of the distal nephron in ischemic kidneys. Cells of the glomerulus and proximal tubules were negative for JE antigen. In contrast to the increase in JE and KC mRNA, steady-state levels of uromodulin (Tamm Horsfall) mRNA, a cytokine binding protein also made by the thick ascending limb, declined to virtually undetectable levels by 24 h after ischemia. Thus the increases in JE and KC are not generalized phenomena. These studies demonstrate that the kidney rapidly expresses genes encoding leukocyte chemoattractants in response to ischemia. JE and KC may serve the renal regenerative response either by promoting the movement of cells along the basement membrane of injured tubules or by attracting leukocytes into the ischemic kidney. The decline of the cytokine binding Tamm-Horsfall protein may also increase the activity of locally generated or filtered cytokines within the kidney.