Nucleosome effects on mesangial cell matrix and proliferation: a possible role in early lupus nephritis.

BACKGROUND

Oligonucleosomes (ON) have been demonstrated in the circulation and biopsies of lupus nephritis patients. Their presence as immune complexes is an early and persistent finding in lupus nephritis as are changes in mesangial matrix. Since ON competitively bind to glomerular mesangial cells (MC) in a receptor-like fashion, the purpose of our study was to investigate what effects ON have on MC matrix and proliferation.

METHODS

Rat and mouse MCs grown with ON or DNA for 1 week were dissociated from their matrices with Triton-X and their proteins were determined. MC collagen production, using collagenase sensitive 3H-proline incorporation, was measured after 48-hour incubation with ON and DNA. Similar experiments using 10-fold excess DNA were done to assess its blocking effect on ON induced collagen synthesis. ON interaction with matrix was evaluated by incubated 125I-ON with MC matrix grown with ON or media alone for 1 week.

RESULTS

MCs stimulated by ON but not DNA significantly increased total matrix protein, total collagen and specifically, collagen type I synthesis. DNA inhibited ON-stimulated collagen synthesis. MC matrix incubated with ON binds 3 times more 125I-ON than matrix generated in media alone. Histone, a major component of nucleosomes, significantly increased 3H-thymidine incorporation.

CONCLUSIONS

Oligonucleosomes, both qualitatively and quantitatively, influence mesangial cell function. These findings for the first time suggest ON to be pathogenic independent of their IC construct. DNA inhibition of ON induced mesangial matrix changes suggests participation of the ON/DNA receptor. Increased production of collagen type I may contribute to glomerulosclerosis.