Glomerulonephritides which progress to chronic renal failure invariably become associated with a substantial degree of interstitial involvement. Previous work in our laboratory, using human biopsy material and in situ hybridization, has suggested a role for expression of complement genes in proximal tubular epithelial cells in this process.

Six weeks old C57/B6 mice received daily intraperitoneal horse spleen apoferritin (HSA 4mg) with thrice-weekly LPS (.05 mg); Controls received.15 M NaCl. Control and treated animals were sacrified weekly for 6 weeks, after blood and urine specimens were obtained. Tissue samples were secured for histology, immunohistochemistry, and in situ hybridization, using a 500 bp 35S riboprobe generated from a murine C3 cDNA.

Treated animals developed evidence of significant chronic disease with proteinuria, hematuria, and uremia (mean BUN at 6 weeks 50 mg/dl treated vs 21 mg/dl control). A mild glomerulonephritis was present at 2 weeks, with significant proliferative glomerulonephritis at 4 weeks, progressing to chronic disease with tubulointerstitial changes at 6 weeks. Changes at each time period were uniform between animals.

C3 mRNA was first detected by in situ hybridization at 3 weeks. As in human disease, message was restricted to proximal tubular and peri-glomerular epithelial cells. Presence of C3 message preceded the development of interstitial inflammation and fibrosis by 1-2 weeks, and its location and intensity paralleled the evolving interstitial disease. Although extensive mesangial C3 protein deposits appeared early, there was never C3 message in glomeruli or infiltrating cells. Before C3 message became apparent, two cytokines known to upregulate C3 transcription in vitro, IL-1 and IL-6, were detected by immunohistochemistry.

The temporal sequence in this model is consistent with our hypothesis that local synthesis and activation of C3 in tubular epithelium is important to the interstitial component of chronic glomerulonephritis. The process is independent of the deposition of circulating complement in the glomerulus, but may be triggered by glomerular cytokines. The latter probably gain access to the tubular epithelium via the vasa rectae or urine.