Search for genes expressed during progression and recovery in the diseased kidney

Abstract

Kidneys can recovery from some type of injury. After an acute glomerulonephritis or a short-term ischemia, damaged glomerulus or tubules recover their normal structures with proliferation of the survived cells and infiltration of extrarenal cells. On the other hand, a prolonged or continuous injury leads to a progressive renal disease. We have investigated molecular events in reversible and irreversible renal diseases and have made efforts to identify genes pivotal in promoting regeneration or progression of the renal diseases. To identify genes responsible for kidney regeneration, we surveyed the expression pattern of the development genes in ischemia-reperfusion model of rat kidney. The regeneration, molding, and maturation of the restored epithelium after renal ischemia injury have many parallels to the growth and maturation that takes place during kidney organogenesis. We found that leukemia inhibitory factor (LIF) and its receptor (LIFR) expression were up-regulated during the recovery phase after ischemia insult. The increased expression of LIF and LIFR was most marked in the outer medulla, especially in the S3 segment of the proximal tubules. In cultured rat renal epithelial NRK52E cells, LIF expression was enhanced during recovery after adenosine triphosphate (ATP) depletion. Blockade of endogenous LIF with a neutralizing antibody significantly reduced the cell number and DNA synthesis during the recovery period. These results suggest that LIF participates in the regeneration process after tubular injury [Yoshino J, Monkawa T, Tsuji M, et al : Leukemia inhibitory factor is involved in tubular regeneration after experimental acute renal failure. J Am Soc Nephrol 14:3090-3101, 2003]. To search for genes playing important roles in progression of renal diseases, we compared gene expression profiles between an irreversible model and a reversible model of anti-Thy-1 glomerulonephritis using a microarray technology. A single intravenous injection of anti-Thy-1 monoclonal antibody 1-22-3 is known to cause a reversible mesangial proliferative glomerulonephritis. However, monoclonal antibody 1-22-3 injection followed by unilateral nephrectomy leads to progressive glomerulosclerosis with an irreversible course. Among 4854 rat genes on the microarray slide, 189 genes were differentially expressed. The differentially expressed genes were classified into five clusters based on their expression patterns. One of the clusters included genes the expression of which was markedly up-regulated in the irreversible model. The expression levels of the genes belonging to the cluster were low in normal kidney and increased along with disease peaked at day 14, and the up-regulation was more pronounced in the irreversible model than the reversible model. This cluster included collagen type1, laminin, osteopontin, kidney injury molecule-1 (KIM-1), and thymosin β10. These molecules can be new therapeutic targets for slowing the progression of renal diseases or accelerating repair of the injured kidney.