CHEMOKINE EXPRESSION IN EXPERIMENTAL TUBULOINTERSTITIAL NEPHRITIS

Chemokines may be important in the pathogenesis of leukocyte infiltrat ion in tubulointerstitial nephritis associated with glomerular disease , We studied the renal cortical expression of the C-C (macrophage infl ammatory protein-1 alpha (MIP-1 alpha)), monocyte chemotactic protein- 1 (MCP-1), and RANTES) and C-X-C (interferon-inducible protein-10 (IP- 10), MIP-2, and cytokine-induced neutrophil chemoattractant (CINC)) ch emokines 4, 6, 8, 10, 14, and 21 days after the induction of puromycin aminonucleoside (PAN) nephrosis. There was a 7- to 10-fold increase i n the steady state mRNA expression of IP-10 and MCP-1 in the renal cor tex of rats 6 to 8 days after the administration of PAN that declines thereafter reaching control values by day 21, The site of IP-10 and MC P-1 mRNA production was localized to intrinsic tubulointerstitial cell s and not to infiltrating monocytes or macrophages, By comparison, the re was a low basal expression of RANTES mRNA in the renal cortex of ne phrotic rats that did not differ from those of control rats. In contra st, CINC, MIP-2, and MIP-1 alpha mRNAs were not detected, Translation of MCP-1 mRNA into protein was confirmed with an ELISA. These changes in chemokine gene expression were associated with a tubulointerstitial T lymphocyte and macrophage infiltration beginning on day 6 that peak ed on day 10, Administration of a neutralizing Ab to rat MCP-1 (n = 5) beginning on day 4 resulted in a 45% decline in tubulointerstitial ma crophage infiltration from 8.4 +/- 1.3% to 4.6 +/- 0.4% (p < 0.001) on day 6, These data provide evidence that MCP-1, and possibly IP-10, ar e important in the pathogenesis of monocyte/macrophage infiltration in the tubulointerstitial nephritis associated with PAN nephrosis.