Glomerulonephritis has been estimated to cause 30% of all end stage renal disease in the United States. The progression of renal dysfunction in glomerulonephritis best correlates clinicopathologically not with glomerular changes but with interstitial changes. One of the earliest interstitial changes is the development of a mononuclear cell infiltrate. The cells of this infiltrate, which are predominantly CD4+ T cells and monocytes, have pathologic significance and contribute to the progression of interstitial fibrosis and scarring. It is not known how glomerular injury induces this infiltrate in the tubulointerstitial space. One hypothesis, however, is that injured glomeruli release cytokines which activate interstitial cells. These cells in turn produce chemoattractants for the inflammatory cells which form the interstitial infiltrate. RANTES, a chemoattractant in the chemokine superfamily, is a candidate for a role in the formation of these infiltrates based upon its specificity. To test the hypothesis that RANTES secretion from cells of the renal interstitium is responsible for the formation of the interstitial infiltrates seen in glomerulonephritis, the regulation of RANTES production by cells of the renal interstitium will be examined at a molecular, cellular, and organismal level. At the molecular level, the RANTES promoter will be analyzed to determine the promoter elements responsible for cytokine and tissue specific regulation. At the cellular level, the interstitial cells that secrete RANTES will be determined and the glomerular-derived substances that induce these cells to secrete RANTES will be defined. On the animal level, RANTES deficiency or RANTES overproduction will be evaluated for their effects on renal inflammation. A Rantes-deficient mouse will be created using homologous recombination in embryonic stem cells. The progression of experimentally induced glomerulonephritis in this mouse will then be evaluated in order to determine if Rantes is necessary for the formation of the inflammatory infiltrate. In addition, a transgenic mouse which over-expresses RANTES in the proximal tubule will be made and the composition and extent of the interstitial infiltrate evaluated. These experiments should better define the biological role of RANTES in renal inflammation.
| Danoff, T M; Chiang, M; Janne, P A et al. (1997) Screening for homologous recombination in ES cells using RT-PCR. Biotechniques 22:22-4, 26 |
